Pyrrolo-naphthyl acids and methods for using them

ABSTRACT

The present invention relates to pyrrolo-naphthyl compounds of the formula  
                 
and methods of using them to modulate PAI-1 expression and to treat PAI-1 related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/208,775, filed Aug. 22, 2005, claiming the benefit of provisionalapplication Ser. No. 60/603,766 filed on Aug. 23, 2004, each of which isincorporated herein by reference in its entirety.

BACKGROUND

The present invention relates generally to pyrrolo-napthyl acids, suchas pyrrolo-5-yl-naphthyl]oxyalkyl-acids, and methods of using them.

The serine protease inhibitor PAI-1 is one of the primary inhibitors ofthe fibrinolytic system. The fibrinolytic system includes the proenzymeplasminogen, which is converted to the active enzyme, plasmin, by one oftwo tissue type plasminogen activators, t-PA or u-PA. PAI-1 is theprincipal physiological inhibitor of t-PA and u-PA. One of plasmin'smain functions in the fibrinolytic system is to digest fibrin at thesite of vascular injury. The fibrinolytic system, however, is not onlyresponsible for the removal of fibrin from circulation but is alsoinvolved in several other biological processes including ovulation,embryogenesis, intima proliferation, angiogenesis, tumorigenesis, andatherosclerosis.

Elevated levels of PAI-1 have been associated with a variety of diseasesand conditions including those associated with impairment of thefibrinolytic system. For example, elevated levels of PAI-1 have beenimplicated in thrombotic diseases, e.g., diseases characterized byformation of a thrombus that obstructs vascular blood flow locally ordetaches and embolizes to occlude blood flow downstream. (Krishnamurti,Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276(1991); Carmeliet, Journal of Clinical Investigation, 92, 2756 (1993),Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)).Antibody neutralization of PAI-1 activity resulted in promotion ofendogenous thrombolysis and reperfusion (Biemond, Circulation, 91, 1175(1995); Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1have also been implicated in diseases such as polycystic ovary syndrome(Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563(2000)), bone loss induced by estrogen deficiency (Daci, Journal of Boneand Mineral Research, 15, 8, 1510 (2000)), cystic fibrosis, diabetes,chronic periodontitis, lymphomas, diseases associated with extracellularmatrix accumulation, malignancies and diseases associated withneoangiogenesis, inflammatory diseases, vascular damage associated withinfections, and diseases associated with increased uPA levels such asbreast and ovarian cancer.

In view of the foregoing, there exists a need for inhibitors of PAI-1activity and methods of using them to modulate PAI-1 expression oractivity, for example, in treating disorders associated with elevatedPAI-1 levels.

SUMMARY

In one aspect, the present invention relates to pyrrolo-naphthyl acidsof the following formula:

or solvates, hydrates or pharmaceutically acceptable salt or ester formsthereof; wherein:

Ar is aryl or heteroaryl;

R₁ is hydrogen, C₁-C₁₂ alkyl, C₆₋₁₄ aryl, C₆₋₁₄ar(C₁₋₆)alkyl,—(CH₂)_(p)-heteroaryl, —(CH₂)_(p)—CO-aryl, —(CH₂)_(p)—CO-heteroaryl,—(CH₂)_(p)—CO—(C₁-C₆)alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, or C₃-C₈cycloalkyl.

R₂ and R₃ are independently hydrogen, C₁-C₁₂ alkyl, C₆₋₁₄ aryl,C₆₋₁₄ar(C₁₋₆)alkyl, —(CH₂)_(p)-heteroaryl, halogen, C₁-C₆ alkoxy,aralkyl, alkoxyaryl, nitro, carboxy(C₁-C₆ alkyl), carbamide, carbamate,or C₃-C₈ cycloalkyl;

R₄ is —CH(R₆)(CH₂)_(n)R₅, —C(CH₃)₂R₆, —CH(R₅)(CH₂)_(n)R₆, —CH(R₅)C₆H₄R₆,—CH(R₅)C₆H₃(CO₂H)₂, CH(R₅)C₆H₂(CO₂H)₃, or an acid mimic;

R₅ is hydrogen, C₁-C₆ alkyl, C₆-C₁₂ aryl, aralkyl, C₃-C₈ cycloalkyl, or—(CH₂)_(n)(R₇);

R₆ is CO₂H, tetrazole, or PO₃H;

R₇ is

n is from 0 to 6;

p is from 0 to 3;

b is from 0 to 6; and

a is from 0 to 6.

The present invention further provides, inter alia, methods of usingpyrrolo-napthyl acids to, for example, modulate PAI-1 expression and/oractivity. In certain methods, a therapeutically effective amount of oneor more compounds of the present invention is administered to a subjectto treat a PAI-1 related disorder. Examplary methods are those thatinvolve inhibiting PAI-1 activity in the subject, such as thatassociated with impairment of the fibrinolytic system. In certainembodiments, one or more compounds of the present invention isadministered to a subject to treat thrombosis, e.g., venous thrombosis,arterial thrombosis, cerebral thrombosis, and deep vein thrombosis,atrial fibrillation, pulmonary fibrosis, thromboembolic complications ofsurgery, cardiovascular disease, e.g., myocardial ischemia,atherosclerotic plaque formation, chronic obstructive pulmonary disease,renal fibrosis, polycystic ovary syndrome, Alzheimer's disease, orcancer.

DETAILED DESCRIPTION

A. General Overview

The present invention provides novel compounds that preferably inhibitPAI-1 activity, processes for preparing such compounds, pharmaceuticalcompositions containing such compounds, and methods for using suchcompounds, for example, in medical therapies. Preferred compounds haveproperties that are useful for prevention and/or inhibition of a widevariety of diseases and disorders including those involving theproduction and/or action of PAI-1. These include disorders resultingfrom impairment of the fibrinolytic system including, but not limitedto, thrombosis, coronary heart disease, renal fibrosis, atheroscleroticplaque formation, pulmonary disease, myocardial ischemia, atrialfibrillation, coagulation syndromes, thromboembolic complications ofsurgery, peripheral arterial occlusion and pulmonary fibrosis. Otherdisorders include, but are not limited to, polycystic ovary syndrome,Alzheimer's disease, and cancer.

The terms “alkyl” and “alkylene,” as used herein, whether used alone oras part of another group, refer to substituted or unsubstitutedaliphatic hydrocarbon chains, the difference being that alkyl groups aremonovalent (i.e., terminal) in nature whereas alkylene groups aredivalent and typically serve as linkers. Both include, but are notlimited to, straight and branched chains containing from 1 to about 12carbon atoms, preferably 1 to about 6 carbon atoms, unless explicitlyspecified otherwise. For example, methyl, ethyl, propyl, isopropyl,butyl, i-butyl and t-butyl are encompassed by the term “alkyl.”Specifically included within the definition of “alkyl” are thosealiphatic hydrocarbon chains that are optionally substituted.Accordingly, the alkyl groups described herein refer to bothunsubstituted or substituted groups. Representative optionalsubstituents include, but are not limited to, halogens, —CN, hydroxy,oxo (═O), acyloxy, alkoxy, amino, amino substituted by one or two alkylgroups of from 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy offrom 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbonatoms, and trihalomethyl. Preferred substituents include halogens, —CN,—OH, oxo (═O), and amino groups.

The carbon number as used in the definitions herein refers to carbonbackbone and carbon branching, but does not include carbon atoms of thesubstituents, such as alkoxy substitutions and the like.

The term “alkenyl”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted aliphatichydrocarbon chain and includes, but is not limited to, straight andbranched chains having 2 to about 10 carbon atoms (unless explicitlyspecified otherwise) and containing at least one double bond.Preferably, the alkenyl moiety has 1 or 2 double bonds. Preferably, thealkenyl moiety has about 2 to about 7 carbon atoms. Such alkenylmoieties can exist in the E or Z conformations and the compounds of thisinvention include both conformations. Specifically included within thedefinition of “alkenyl” are those aliphatic hydrocarbon chains that areoptionally substituted. Accordingly, the alkenyl groups described hereinrefer to both unsubstituted or substituted groups. Representativeoptional substituents include, but are not limited to, halogens, —CN,hydroxy, acyloxy, alkoxy, amino, amino substituted by one or two alkylgroups of from 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy offrom 1 to 6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbonatoms, and trihalomethyl. Heteroatoms, such as O or S attached to analkenyl should not be attached to a carbon atom that is bonded to adouble bond. Preferred substituents include halogens, —CN, —OH, andamino groups.

The term “alkynyl”, as used herein, whether used alone or as part ofanother group, refers to a substituted or unsubstituted aliphatichydrocarbon chain and includes, but is not limited to, straight andbranched chains having 2 to about 10 carbon atoms (unless explicitlyspecified otherwise) and containing at least one triple bond.Preferably, the alkynyl moiety has about 2 to about 7 carbon atoms. Incertain embodiments, the alkynyl can contain more than one triple bondand, in such cases, the alkynyl group must contain at least four carbonatoms. Specifically included within the definition of “alkynyl” arethose aliphatic hydrocarbon chains that are optionally substituted.Accordingly, the alkynyl groups described herein refer to bothunsubstituted or substituted groups. Representative optionalsubstituents include, but are not limited to, halogens, —CN, hydroxy,acyloxy, alkoxy, amino, amino substituted by one or two alkyl groups offrom 1 to 6 carbon atoms, aminoacyl, acylamino, thioalkoxy of from 1 to6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, andtrihalomethyl. Preferred substituents include halogens, —CN, —OH, andamino groups. Heteroatoms, such as O or S attached to an alkynyl shouldnot be attached to the carbon that is bonded to a triple bond.

The term “cycloalkyl” as used herein, whether alone or as part ofanother group, refers to a substituted or unsubstituted alicyclichydrocarbon group having 3 to about 20 carbon atoms (unless explicitlyspecified otherwise), preferably 3 to about 6 carbon atoms. Specificallyincluded within the definition of “cycloalkyl” are those alicyclichydrocarbon groups that are optionally substituted. Accordingly, thecycloalkyl groups described herein refer to both unsubstituted orsubstituted groups. Representative optional substituents include, butare not limited to, hydroxy, oxo (═O), acyloxy, alkoxy, amino, aminosubstituted by one or two alkyl groups of from 1 to 6 carbon atoms,aminoacyl, acylamino, thioalkoxy of from 1 to 6 carbon atoms,substituted thioalkoxy of from 1 to 6 carbon atoms, and trihalomethyl.

The term “aryl”, as used herein, whether used alone or as part ofanother group, is defined as a substituted or unsubstituted aromatichydrocarbon ring group having 5 to about 50 carbon atoms (unlessexplicitly specified otherwise) with from about 6 to about 14 carbonatoms being preferred, more preferably from about 6 to about 12 carbonatoms. The “aryl” group can have a single ring or multiple condensedrings. The term “aryl” includes, but is not limited to phenyl,α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl,fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. Specificallyincluded within the definition of “aryl” are those aromatic groups thatare optionally substituted. Accordingly, the aryl groups (e.g., phenyl,naphthyl, and fluorenyl) described herein refer to both unsubstituted orsubstituted groups. In representative embodiments of the presentinvention, the “aryl” groups are optionally substituted with from 1 to 5substituents selected from the group consisting of acyloxy, hydroxy,acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, C₃-C₆cycloalkyl, —(CH₂)_(p)—C₃-C₆ cycloalkyl, C₁-C₃ perfluoroalkyl, C₁-C₃perfluoroalkoxy, —(CH₂)_(p)-phenyl, —O(CH₂)_(p)-phenyl, amino, aminosubstituted by one or two alkyl groups of from 1 to 6 carbon atoms,aminoacyl, acylamino, azido, cyano, halo, nitro, thioalkoxy of from 1 to6 carbon atoms, substituted thioalkoxy of from 1 to 6 carbon atoms, andtrihalomethyl. For example, the “aryl” groups can be optionallysubstituted with from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy, hydroxy, C₃-C₆ cycloalkyl, —(CH₂)_(p)—C₃-C₆ cycloalkyl, halogen,C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy, —(CH₂)_(p)-phenyl, and—O(CH₂)_(p)-phenyl. In these embodiments, the phenyl group of—(CH₂)_(p)-phenyl and —O(CH₂)_(p)-phenyl can be optionally substitutedwith, for example, from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy, —(CH₂)_(p)-phenyl, halogen, trifluoromethyl or trifluoromethoxy.Preferred aryl groups include phenyl and naphthyl. P is an integer from0 to 3. Preferred substituents on the aryl groups herein include C₁-C₆alkyl, C₁-C₆ alkoxy, halo, cyano, nitro, trihalomethyl, and C₁-C₆thioalkoxy.

As used herein, the term “heteroaryl”, whether used alone or as part ofanother group, is defined as a substituted or unsubstituted aromaticheterocyclic ring system. Heteroaryl groups can have, for example, fromabout 3 to about 50 carbon atoms (unless explicitly specifiedotherwise), with from about 4 about 10 being preferred. In someembodiments, heteroaryl groups are aromatic heterocyclic ring systemshaving 5 to 14 ring atoms and containing carbon atoms and 1, 2, 3 or 4oxygen, nitrogen or sulfur heteroatoms. Representative heteroaryl groupsare furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole,isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine,pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole,1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole,1-methyltetrazole, benzoxazole, benzothiazole, benzofuran,benzothiophene, benzisoxazole, benzimidazole, N-methylbenzimidazole,azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline.Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidineor pyridizine rings that are (a) fused to a 6-membered aromatic(unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a5- or 6-membered aromatic (unsaturated) heterocyclic ring having twonitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated)heterocyclic ring having one nitrogen atom together with either oneoxygen or one sulfur atom; or (d) fused to a 5-membered aromatic(unsaturated) heterocyclic ring having one heteroatom selected from O, Nor S. Specifically included within the definition of “heteroaryl” arethose aromatic groups that are optionally substituted. Accordingly, theheteroaryl groups (e.g., furanyl, thiophenyl, benzofuranyl,benzothiophenyl, indolyl, pyrazolyl, and oxazolyl) described hereinrefer to both unsubstituted or substituted groups. In representativeembodiments of the present invention, the “heteroaryl” groups areoptionally substituted with from 1 to 5 substituents selected from thegroup consisting of acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms,alkynyl of 2 to 6 carbon atoms, C₃-C₆ cycloalkyl, —(CH₂)_(p)—C₃-C₆cycloalkyl, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy,—(CH₂)_(p)-phenyl, —O(CH₂)_(p)-phenyl, amino, amino substituted by oneor two alkyl groups of from 1 to 6 carbon atoms, aminoacyl, acylamino,azido, cyano, halo, nitro, thioalkoxy of from 1 to 6 carbon atoms,substituted thioalkoxy of from 1 to 6 carbon atoms, and trihalomethyl.In some embodiments of the present invention, the “heteroaryl” groupscan be optionally substituted with from 1 to 3 groups selected fromC₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, C₃-C₆ cycloalkyl, —(CH₂)_(p)—C₃-C₆cycloalkyl, halogen, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy,—(CH₂)_(p)-phenyl, and —O(CH₂)_(p)-phenyl. In these embodiments, thephenyl group of —(CH₂)_(p)-phenyl and —O(CH₂)_(p)-phenyl can beoptionally substituted with, for example, from 1 to 3 groups selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl, halogen, trifluoromethyl ortrifluoromethoxy. P is an integer of from 0 to 3. Preferred heteroarylsof the present invention include substituted and unsubstituted furanyl,thiophenyl, benzofuranyl, benzothiophenyl, indolyl, pyrazolyl, andoxazolyl.

The term “alkoxy” as used herein, refers to the group R_(a)—O— whereinR_(a) is an alkyl group as defined above. The term “thioalkoxy” as usedherein, refers to the group —O—R_(a)—S— wherein R_(a) is an alkyl groupas defined above. Specifically included within the definition of“alkoxy” and “thioalkoxy” are those groups that are optionallysubstituted. Accordingly, the alkoxy and thioalkoxy groups describedherein refer to both unsubstituted or substituted groups. Preferredsubstituents on alkoxy and thioalkoxy groups include halogens, —CN, —OH,and amino groups.

The term “alkoxyaryl” as used herein, refers to the group R_(a)—O-aryl-wherein R_(a) is an alkyl group as defined above and aryl is as definedabove.

The term “arylalkyl” or “aralkyl” refers to the group —R_(a)—R_(b),where R_(a) is an alkylene group as defined above, substituted by R_(b),an aryl group. Preferred aralkyl groups include C₆₋₁₄ar(C₁₋₆)alkylgroups. Aralkyl groups of the present invention are optionallysubstituted. For example, in preferred embodiments, the benzyl groups ofthe present invention are optionally substituted with from 1 to 3 groupsselected from C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, C₃-C₆ cycloalkyl,—(CH₂)_(p)—C₃-C₆ cycloalkyl, halogen, C₁-C₃ perfluoroalkyl, C₁-C₃perfluoroalkoxy, —(CH₂)_(p)-phenyl, and —O(CH₂)_(p)-phenyl. Examples ofarylalkyl moieties include, but are not limited to, benzyl,1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and thelike

The term “perfluoroalkyl”, as used herein, whether used alone or as partof another group, refers to a saturated aliphatic hydrocarbon having 1to 6 carbon atoms and two or more fluorine atoms and includes, but isnot limited to, straight or branched chains, such as —CF₃, —CH₂CF₃,—CF₂CF₃ and —CH(CF₃)₂.

The term “halogen” or “halo” refers to chlorine, bromine, fluorine, andiodine.

The term “carbamide,” as used herein, refers to the group —C(O)NR′R″where R′ and R″ are independently hydrogen, alkyl, aryl or cycloalkyl asdefined herein.

The term “carbamate,” as used herein, refers to the group —OC(O)NR′R″where R′ and R″ are independently hydrogen, alkyl, aryl or cycloalkyl asdefined herein.

The term “acyl” refers to a radical of the formula RC(O)—, where R ishydrogen, alkyl, aryl, or cycloalkyl as defined herein. Suitable acylradicals include formyl, acetyl, propionyl, and the like.

The term “acyloxy” refers to radicals of the formula RC(O)O—, where R ishydrogen, alkyl, aryl or cycloalkyl as defined herein. Suitable acyloxyradicals include CH₃COO—, CH₃CH₂COO—, benzoyloxy, and the like.

The term “acylamino” refers to radicals of the formula RC(O)NH— where Ris hydrogen, alkyl, aryl, or cycloalkyl as defined herein.

The term “aminoacyl” refers to radicals of the formula —(R)₀₋₃C(O)NH2where R is alkylene as previously described.

The term “treating” or “treatment” refers to any indicia of success inamelioration of an injury, pathology, or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the injury, pathology, or conditionmore tolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating; orimproving a subject's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination,neurological examination, and/or psychiatric evaluation. “Treating” or“treatment of a PAI-1 related disorder” includes preventing the onset ofsymptoms in a subject that may be predisposed to a PAI-1 relateddisorder but does not yet experience or exhibit symptoms of the disorder(prophylactic treatment), inhibiting the symptoms of the disorder(slowing or arresting its development), providing relief from thesymptoms or side-effects of the disorder (including palliativetreatment), and/or relieving the symptoms of the disorder (causingregression). Accordingly, the term “treating” includes theadministration of the compounds or agents of the present invention to asubject to prevent or delay, to alleviate, or to arrest or inhibitdevelopment of the symptoms or conditions associated with PAI-1 relateddisorders, e.g., tumor growth associated with cancer. A skilled medicalpractitioner will know how to use standard methods to determine whethera patient is suffering from a disease associated with enhanced levelsand/or activity of PAI-1, e.g., by examining the patient and determiningwhether the patient is suffering from a disease known to be associatedwith elevated PAI-1 levels or activity or by assaying for PAI-1 levelsin blood plasma or tissue of the individual suspected of suffering froma PAI-1 related disease and comparing PAI-1 levels in the blood plasmaor tissue of the individual suspected of suffering from a PAI-1 relateddisease to PAI-1 levels in the blood plasma or tissue of a healthyindividual. Methods known in the art for the detection of nucleic acidsand proteins can be used for determining PAI-1 levels in a subject,e.g., PCR, northern and Southern blots, dot blots, nucleic acid arrays,western blots, immunoassays such as immunoprecipitation, ELISA,proteomics assays, and the like. Increased PAI-1 levels are indicativeof disease.

In healthy individuals, PAI-1 is found at low levels in the plasma(e.g., 5-10 ng/mL), but it is elevated significantly in a number ofdiseases, including, for example, atherosclerosis (Schneiderman J. et.al, Proc Natl Acad Sci 89: 6998-7002, 1992) deep vein thrombosis(Juhan-Vague I, et. al, Thromb Haemost 57: 67-72, 1987), and non-insulindependent diabetes mellitus (Juhan-Vague I, et. al, Thromb Haemost 78:565-660, 1997). PAI-1 stabilizes both arterial and venous thrombi,contributing respectively to coronary arterial occlusion inpost-myocardial infarction (Hamsten A, et. al. Lancet 2:3-9, 1987), andvenous thrombosis following post-operative recovery from orthopedicsurgery. (Siemens H J, et. al, J Clin Anesthesia 11: 622-629, 1999).Plasma PAI-1 is also elevated, for example, in postmenopausal women, andhas been proposed to contribute to the increased incidence ofcardiovascular disease in this population (Koh K et. al, N Engl J Med336: 683-690, 1997).

The term “PAI-1 related disorder or disease” refers to any disease orcondition that is associated with increased or enhanced expression oractivity of PAI-1 or increased or enhanced expression or activity of agene encoding PAI-1. Examples of such increased activity or expressioninclude the following: activity of the protein or expression of the geneencoding the protein is increased above the level of that in normalsubjects; activity of the protein or expression of the gene encoding theprotein is in an organ, tissue or cell where it is not normally detectedin normal subjects (i.e. spatial distribution of the protein orexpression of the gene encoding the protein is altered); activity of theprotein or expression of the gene encoding the protein is increased whenactivity of the protein or expression of the gene encoding the proteinis present in an organ, tissue or cell for a longer period than in anormal subjects (i.e., duration of activity of the protein or expressionof the gene encoding the protein is increased). A normal subject is asubject not suffering from a PAI-1 related disorder or disease.

The term “pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic, and desirable, and includes excipients that areacceptable for veterinary use as well as for human pharmaceutical use.Such excipients can be solid, liquid, semisolid, or, in the case of anaerosol composition, gaseous.

“Pharmaceutically acceptable salts and esters” refers to salts andesters that are pharmaceutically acceptable and have the desiredpharmacological properties. Such salts include, for example, salts thatcan be formed where acidic protons present in the compounds are capableof reacting with inorganic or organic bases. Suitable inorganic saltsinclude, for example, those formed with the alkali metals or alkalineearth metals, e.g. sodium and potassium, magnesium, calcium, andaluminum. Suitable organic salts include, for example, those formed withorganic bases such as the amine bases, e.g. ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like. Pharmaceutically acceptable salts can also include acidaddition salts formed from the reaction of amine moieties in the parentcompound with inorganic acids (e.g. hydrochloric and hydrobromic acids)and organic acids (e.g. acetic acid, citric acid, maleic acid, and thealkane- and arene-sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid). Pharmaceutically acceptable esters include estersformed from carboxy, sulfonyloxy, and phosphonoxy groups present in thecompounds, e.g. C₁₋₆ alkyl esters.

When there are two acidic groups present, a pharmaceutically acceptablesalt or ester can be a mono-acid-mono-salt or ester or a di-salt orester; and similarly where there are more than two acidic groupspresent, some or all of such groups can be salified or esterified.Compounds of the invention can be present in unsalified or unesterifiedform, or in salified and/or esterified form, and the naming of suchcompounds is intended to include both the original (unsalified andunesterified) compound and its pharmaceutically acceptable salts andesters. Also, certain compounds can be present in more than onestereoisomeric form, and the naming of such compounds is intended toinclude all single stereoisomers and all mixtures (whether racemic orotherwise) of such stereoisomers.

The terms “inhibitor,” “activator,” and “modulator” as used inconnection with expression or activity refer to inhibitory, activating,or modulating molecules, respectively. Inhibitors of the presentinvention include compounds or compositions that inhibit expression ofPAI-1 or bind to, partially or totally block stimulation, decrease,prevent, delay activation, inactivate, desensitize, or down regulate theactivity of PAI-1. Samples or assays comprising PAI-1 can be treatedwith a composition of the present invention and compared to controlsamples without a composition of the present invention. Control samples(untreated with compositions of the present invention) can be assigned arelative activity value of 100%. In certain embodiments, inhibition ofPAI-1 is achieved when the activity value relative to the control isabout 80% or less, optionally 50% or 25, 10%, 5% or 1%.

The terms “pharmaceutically acceptable”, “physiologically tolerable” andgrammatical variations thereof; as they refer to compositions, carriers,diluents and reagents, are used interchangeably and represent that thematerials are capable of administration to or upon a human without theproduction of undesirable physiological effects such as nausea,dizziness, gastric upset and the like which would be to a degree thatwould prohibit administration of the compound.

A “therapeutically effective amount” or “pharmaceutically effectiveamount” means an amount that, when administered to a subject fortreating a disease, is sufficient to effect treatment for that disease.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and formulations of thepresent invention.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

B. Pyrrolo-Naphthyl Acids

As noted above, the compounds of the present invention include those ofthe following formula:

or solvates, hydrates or pharmaceutically acceptable salt or ester formsthereof; wherein:

Ar is aryl or heteroaryl;

R₁ is hydrogen, C₁-C₁₂ alkyl, C₆₋₁₄ aryl, C₆₋₁₄ar(C₁₋₆)alkyl,—(CH₂)_(p)-heteroaryl, —(CH₂)_(p)—CO-aryl, —(CH₂)_(p)—CO-heteroaryl,—(CH₂)_(p)—CO—(C₁-C₆)alkyl, aralkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, orC₃-C₈ cycloalkyl;

R₂ and R₃ are independently hydrogen, C₁-C₁₂ alkyl, C₆₋₁₄ aryl,C₆₋₁₄ar(C₁₋₆)alkyl, —(CH₂)_(p)-heteroaryl, halogen, C₁-C₆ alkoxy,alkoxyaryl, nitro, carboxy(C₁-C₆ alkyl), carbamide, carbamate, or C₃-C₈cycloalkyl;

R₄ is —CH(R₆)(CH₂)_(n)R₅, —C(CH₃)₂R₆, —CH(R₅)(CH₂)_(n)R₆, —CH(R₅)C₆H₄R₆,—CH(R₅)C₆H₃(CO₂H)₂, CH(R₅)C₆H₂(CO₂H)₃, or an acid mimic;

R₅ is hydrogen, C₁-C₆ alkyl, C₆-C₁₂ aryl, aralkyl, C₃-C₈ cycloalkyl, or—(CH₂)_(n)(R₇);

R₆ is CO₂H, tetrazole, or PO₃H;

R₇ is

n is from 0 to 6;

p is from 0 to 3;

b is from 0 to 6; and

a is from 0 to 6.

In certain embodiments in the definition of R₁, R₂ and R₃ said C₁-C₁₂alkyl is unsubstituted C₁-C₁₂ alkyl or C₁-C₃ perfluoroalkyl and saidC₁-C₆ alkoxy is unsubstituted C₁-C₆ alkoxy or C₁-C₃ perfluoroalkoxy.

Such pyrrolo-naphthyl acids include the following compounds:

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof; wherein:

Ar, R₁ to R₇, b, n and p are as defined above and R₈, R₁, R₁₀, R₁₁ andR₁₂ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy,C₃-C₆ cycloalkyl, —(CH₂)_(p)—C₃-C₆ cycloalkyl, halogen,—(CH₂)_(p)-phenyl, or —O(CH₂)_(p)-phenyl. In certain embodiments saidC₁-C₆ alkyl is unsubstituted C₁-C₆ alkyl or C₁-C₃ perfluoroalkyl; saidC₁-C₆ alkoxy is unsubstituted C₁-C₆ alkoxy or C₁-C₃ perfluoroalkoxy. Inpreferred compounds, R₈, R₉, R₁₀, R₁₁ and R₁₂ are hydrogen.

In exemplary embodiments of Formulas 1, 2, 3, 4 or 5 the definitionshave one or more, e.g. all, of the following values:

Ar is aryl or heteroaryl;

R₁ is hydrogen, C₁-C₆ alkyl or —(CH₂)_(p)-phenyl;

R₂ and R₃ are independently hydrogen, unsubstituted C₁-C₆ alkyl,phenyl-(CH₂)_(p)—, halogen or C₁-C₃ perfluoroalkyl;

R₄ is —CHR₅CO₂H, —CH₂R₅C₆H₄CO₂H, —CH₂R₅C₆H₃(CO₂H)₂, —CH₂-tetrazole or anacid mimic;

R₅ is hydrogen, optionally substituted phenyl, or optionally substitutedbenzyl;

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof.

In exemplary embodiments the definitions have one or more, e.g. all, ofthe following values:

Ar is phenyl, naphthyl, furanyl, thiophenyl, benzofuranyl,benzothiophenyl, indolyl, pyrazolyl, oxazolyl or fluorenyl;

R₁ is hydrogen, C₁-C₆ alkyl or —(CH₂)_(p)-phenyl;

R₂ and R₃ are independently hydrogen, unsubstituted C₁-C₆ alkyl,phenyl-(CH₂)_(p)—, halogen or C₁-C₃ perfluoroalkyl;

R₄ is —CHR₅CO₂H, —CHR₅C₆H₄CO₂H, —CHR₅C₆H₃(CO₂H)₂, —CH₂-tetrazole or anacid mimic;

R₅ is hydrogen, optionally substituted phenyl, or optionally substitutedbenzyl;

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof.

In some compounds of the present invention, OR₄ is in the 6 positionrelative to the pyrrole ring (the numbering system used is shown inFormula 4).

Compounds of the present invention also include prodrugs andstereoisomers of formulas 1-5.

In certain exemplary embodiments, R₁ is hydrogen, C₁-C₁₂ alkyl, or—(CH₂)_(p)-phenyl wherein the phenyl ring is optionally substituted withC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, trifluoromethyl, ortrifluoromethoxy. In certain compounds, R₁ is hydrogen, C₁-C₆ alkyl or—(CH₂)_(p)-phenyl. For example, in some compounds, R₁ is hydrogen,methyl, phenyl, benzyl or 4-trifluoromethylbenzyl.

In some compounds, R₂ and R₃ are, independently, hydrogen, C₁-C₆ alkyl,halogen, C₁-C₃ perfluoroalkyl, or —(CH₂)_(p)-phenyl wherein the phenylring is optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,trifluoromethyl, or trifluoromethoxy. In certain embodiments of thepresent invention, R₂ is hydrogen and R₃ is hydrogen or halogen. Forexample R₃ is hydrogen or bromine.

In some compounds, R₄ is —CHR₅CO₂H, —CH₂-tetrazole, —CH(R₅)C₆H₄CO₂H,CH(R₅)C₆H₃(CO₂H)₂ or an acid mimic. In certain embodiments, R₄ isunsubstituted CH₂COOH, substituted CH₂COOH, —CH₂-tetrazole or—CH(R₅)C₆H₄CO₂H. In some embodiments, for example R₄ is unsubstitutedCH₂COOH; CH₂COOH wherein the methylene group is substituted with benzyl;—CH₂-tetrazole; or —CH(R₅)C₆H₄CO₂H.

In some compounds of the present invention, R₅ is hydrogen, phenyl orbenzyl.

In some exemplary embodiments, Ar is substituted or unsubstitutedphenyl, naphthyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl,indolyl, pyrazolyl, oxazolyl or fluorenyl. In certain embodiments, Ar isa substituted or unsubstituted phenyl.

Exemplary pyrrolo-napthyl acids of the present invention include, butare not limited to,3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acidor a pharmaceutically acceptable salt or ester form thereof;2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof;5-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole ora pharmaceutically acceptable salt or ester form thereof;5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or apharmaceutically acceptable salt or ester form thereof;2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof;3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid or a pharmaceutically acceptable salt or ester form thereof;5-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]aceticacid or a pharmaceutically acceptable salt or ester form thereof;5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or apharmaceutically acceptable salt or ester form thereof;2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof;4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoicacid or a pharmaceutically acceptable salt or ester form thereof;4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acidor a pharmaceutically acceptable salt or ester form thereof;4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalicacid or a pharmaceutically acceptable salt or ester form thereof;4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acidor a pharmaceutically acceptable salt or ester form thereof.

The present invention also provides compositions comprising thepyrrolo-naphthyl acids of the present invention, including thosecompounds of formulas 1-5 or a stereoisomer or pharmaceuticallyacceptable solvate, hydrate, salt or ester form thereof; and one or morepharmaceutically acceptable carriers, excipients, or diluents. Suchcompositions include pharmaceutical compositions for treating orcontrolling disease states or conditions associated with increased PAI-1activity. In certain embodiments, the compositions comprise mixtures ofone or more pyrrolo-naphthyl acids.

Certain of the compounds of formulas 1-5 contain stereogenic carbonatoms or other chiral elements and thus give rise to stereoisomers,including enantiomers and diastereomers. The present invention includesall of the stereoisomers of formulas 1-5, as well as mixtures of thestereoisomers. Throughout this application, the name of the product,where the absolute configuration of an asymmetric center is notindicated, is intended to embrace the individual stereoisomers as wellas mixtures of stereoisomers.

Where an enantiomer is preferred, it can, in some embodiments, beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound that is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. “Substantially free,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In preferred embodiments, thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments of the invention, the compound is madeup of at least about 99% by weight of a preferred enantiomer. Preferredenantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including high performance liquidchromatography (HPLC) and the formation and crystallization of chiralsalts, or preferred enantiomers can be prepared by methods describedherein. Methods for the preparation of preferred enantiomers aredescribed, for example, in Jacques, et al, Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972).

Exemplary salt forms of the compounds herein include, but are notlimited to, sodium salts and potassium salts. Other exemplary salt formsof these compounds include, but are not limited to, those formed withpharmaceutically acceptable inorganic and organic bases or acids knownin the art. The acids include, for example, acetic, propionic, lactic,citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic,phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable aids when a compound ofthis invention contains a basic moiety. Salt forms prepared usinginorganic bases include hydroxides, carbonates or bicarbonates of thetherapeutically acceptable alkali metals or alkaline earth metals, suchas sodium potassium, magnesium, calcium and the like. Acceptable organicbases include amines, such as benzylamine, mono-, di- andtrialkylamines, preferably those having alkyl groups of from 1 to 6carbon atoms, more preferably 1 to 3 carbon atoms, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,mono-, di-, and triethanolamine. Exemplary salts also include alkylenediamines containing up to 6 carbon atoms, such as hexamethylenediamine;cyclic saturated or unsaturated bases containing up to 6 carbon atoms,including pyrrolidine, piperidine, morpholine, piperazine and theirN-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hydroxyethyl)-piperidine, or pyridine. Quaternary salts can also beformed, such as tetralkyl forms, such as tetramethyl forms,alkyl-alkanol forms, such as methyl-triethanol or trimethyl-monoethanolforms, and cyclic ammonium salt forms, such as N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-di-methylmorpholinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, or N,N-dimethyl-piperidiniumsalt forms. These salt forms can be prepared using the acidiccompound(s) of Formulas 1-2 and procedures known in the art.

Exemplary ester forms of the compounds of this invention include, butare not limited to, straight chain alkyl esters having from 1 to 6carbon atoms or branched chain alkyl groups containing 1 to 6 carbonatoms, including methyl, ethyl, propyl, butyl, 2-methylpropyl and1,1-dimethylethyl esters, cycloalkyl esters, alkylaryl esters, benzylesters, and the like. Other exemplary esters include, but are notlimited to, those of the formula —COOR₁₃ wherein R₁₃ is selected fromthe formula:

wherein R₁₄, R₁₅, R₁₆, and R₁₇ are independently selected from hydrogen,alkyl of from 1 to 10 carbon atoms, aryl of 6 to 12 carbon atoms,arylalkyl of from 6 to 12 carbon atoms; heteroaryl or alkylheteroarylwherein the heteroaryl ring is bound by an alkyl chain of from 1 to 6carbon atoms.

Acids and acid mimics, according to the invention, are defined as protonor hydrogen donating groups. Exemplary acid mimics or mimetics of thepresent invention include pharmaceutically useful carboxylic acids andacid mimics or mimetics known in the art, such as those described in R.Silverman, The Organic Chemistry of Drug Design and Drug Action,Academic Press (1992) and others. Exemplary acid mimics or mimeticsinclude, but are not limited to the following examples, tetrazole,tetronic acid or groups having the formula:

wherein R₁₈ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, —CH₂—(C₃-C₆cycloalkyl), C₃-C₆ cycloalkenyl, —CH₂—(C₃-C₆ cycloalkenyl), optionallysubstituted aryl or heteroaryl groups or optionally substitutedaryl(C₁-C₆)alkyl or heteroaryl(C₁-C₆)alkyl, with the aryl and heteroarylgroups as defined herein.

Preferred compounds of the present invention inhibit PAI-1 activity.Accordingly, the compounds can be used for the treatment, includingprevention, inhibition, and/or amelioration of PAI-1 related disordersin a subject, including, for example, in the treatment of noninsulindependent diabetes mellitus, in the treatment of cardiovascular disease,and in the treatment of thrombotic events including those associatedwith coronary artery and cerebrovascular disease. Using the methods ofthe present invention, a skilled medical practitioner will know how toadminister the compounds of the present invention, including thoserepresented by formulas 1-5, to a subject suffering from any of thediseases associated with increased PAI-1 activity or expression, e.g.,diabetes or cardiovascular disease, in order to effect treatment forthat disease.

In one exemplary embodiment, the compounds of the present invention areadministered to a subject in order to treat disease processes involvingthrombotic and prothrombotic states which include, but are not limitedto, formation of atherosclerotic plaques, venous and arterialthrombosis, myocardial ischemia, atrial fibrillation, deep veinthrombosis, coagulation syndromes, pulmonary thrombosis, cerebralthrombosis, thromboembolic complications of surgery (such as joint orhip replacement), and peripheral arterial occlusion.

Any disease or condition that is associated with increased PAI-1activity or expression in a subject can be treated using the compoundsof the present invention. Exemplary diseases and conditions includestroke, e.g., stroke associated with or resulting from atrialfibrillation; diseases associated with extracellular matrix accumulationincluding, but not limited to, renal fibrosis, chronic obstructivepulmonary disease, polycystic ovary syndrome, restenosis, renovasculardisease, and organ transplant rejection; diseases associated withneoangiogenesis, including, but not limited to, diabetic retinopathy;Alzheimer's disease, e.g., by increasing or normalizing levels ofplasmin concentration in a subject; myelofibrosis with myeloidmetaplasia, e.g., by regulating stromal cell hyperplasia and increasesin extracellular matrix proteins.

The compounds of the present invention can be used to treat, forexample, diabetic nephropathy and renal dialysis associated withnephropathy; malignancies or cancers, including, but not limited to,leukemia, breast cancer and ovarian cancer; tumors, including, but notlimited to, liposarcomas and epithelial tumors; septicemia; obesity;insulin resistance; proliferative diseases, including, but not limitedto, psoriasis; conditions associated with abnormal coagulationhomeostasis; low grade vascular inflammation; cerebrovascular diseases;hypertension; dementia; osteoporosis; arthritis; asthma; heart failure;arrhythmia; angina, including, but not limited to, angina pectoris;atherosclerosis and sequelae; kidney failure; multiple sclerosis;osteoporosis; osteopenia; dementia; peripheral vascular disease;peripheral arterial disease; acute vascular syndromes; microvasculardiseases including, but not limited to, nephropathy, neuropathy,retinopathy and nephrotic syndrome; hypertension; Type I and II diabetesand related diseases; hyperglycemia; hyperinsulinemia; malignantlesions; premalignant lesions; gastrointestinal malignancies; coronaryheart disease, including, but not limited to, primary and secondaryprevention of myocardial infarction, stable and unstable angina, primaryprevention of coronary events, and secondary prevention ofcardiovascular events; and inflammatory diseases, including, but notlimited to, septic shock and the vascular damage associated withinfections.

The compounds of the present invention can also be administered to asubject in combination with a second therapeutic agent, including, butnot limited to, prothrombolytic, fibrinolytic, and anticoagulant agents,or in conjunction with other therapies, for example, proteaseinhibitor-containing highly active antiretroviral therapy (HAART) forthe treatment of diseases which originate from fibrinolytic impairmentand hyper-coagulability of HIV-1 infected patients. In certainembodiments, the compounds of the present invention can be administeredin conjunction with and/or following processes or procedures involvingmaintaining blood vessel patency, including, but not limited to,vascular surgery, vascular graft and stent patency, organ, tissue andcell implantation and transplantation. The compounds of the presentinvention can also be used for the treatment of blood and blood productsused in dialysis, blood storage in the fluid phase, especially ex vivoplatelet aggregation. The compounds of the present invention can also beadministered to a subject as a hormone replacement agent or to reduceinflammatory markers or C-reactive protein. The compounds can beadministered to improve coagulation homeostasis, to improve endothelialfunction, or as a topical application for wound healing, e.g., theprevention of scarring. The compounds of the present invention can beadministered to a subject in order to reduce the risk of undergoing amyocardial revascularization procedure. The present compounds can alsobe added to human plasma during the analysis of blood chemistry inhospital settings to determine the fibrinolytic capacity thereof. Incertain embodiments, the compounds of the present invention can be usedas imaging agents for the identification of metastatic cancers.

C. Synthesis Overview

Compounds of the present invention can be prepared by those skilled inthe art of organic synthesis employing conventional methods that utilizereadily available reagents and starting materials. Representativecompounds of the present invention can be prepared using the followingsynthetic schemes. The skilled practitioner will know how to make use ofvariants of these process steps, which in themselves are well known inthe art. In the following reaction schemes, the substituents areselected from the groups defined above.

D. Pharmaceutical Compositions

In a preferred embodiment, the compounds of the present invention areformulated as pharmaceuticals to treat diseases associated withincreased PAI-1 activity, e.g., by inhibiting PAI-1 activity in asubject.

In general, the compounds of the present invention can be administeredas pharmaceutical compositions by any method known in the art foradministering therapeutic drugs including oral, buccal, topical,systemic (e.g., transdermal, intranasal, or by suppository), orparenteral (e.g., intramuscular, subcutaneous, or intravenousinjection). Compositions can take the form of tablets, pills, capsules,semisolids, powders, sustained release formulations, solutions,suspensions, emulsions, syrups, elixirs, aerosols, or any otherappropriate compositions; and comprise at least one compound of thisinvention in combination with at least one pharmaceutically acceptableexcipient. Suitable excipients are well known to persons of ordinaryskill in the art, and they, and the methods of formulating thecompositions, can be found in such standard references as Alfonso A R:Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton Pa., 1985. Suitable liquid carriers, especially for injectablesolutions, include water, aqueous saline solution, aqueous dextrosesolution, and glycols. In some embodiments of the present invention,pyrrolo-napthyl acids suitable for use in the practice of this inventionwill be administered either singly or in combination with at least oneother compound of this invention. Pyrrolo-napthyl acids can also beadministered with at least one other conventional therapeutic agent forthe disease being treated.

Aqueous suspensions of the invention can contain pyrrolo-napthyl acidsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients can include, for example, a suspendingagent, such as sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a pyrrolo-napthyl acidsin a vegetable oil, such as arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin; or a mixtureof these. The oil suspensions can contain a thickening agent, such asbeeswax, hard paraffin or cetyl alcohol. Sweetening agents can be addedto provide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations of the invention can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan mono-oleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

The compound of choice, alone or in combination with other suitablecomponents, can be made into aerosol formulations (i.e., they can be“nebulized”) to be administered via inhalation. Aerosol formulations canbe placed into pressurized acceptable propellants, such asdichlorodifluoromethane, propane, nitrogen, and the like.

Formulations suitable for parenteral administration, such as, forexample, by intraarticular (in the joints), intravenous, intramuscular,intradermal, intraperitoneal, and subcutaneous routes, include aqueousand non-aqueous, isotonic sterile injection solutions, which can containantioxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.Among the acceptable vehicles and solvents that can be employed arewater and Ringer's solution, an isotonic sodium chloride. In addition,sterile fixed oils can conventionally be employed as a solvent orsuspending medium. For this purpose any bland fixed oil can be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid can likewise be used in the preparation of injectables.These solutions are sterile and generally free of undesirable matter.Where the compounds are sufficiently soluble they can be dissolveddirectly in normal saline with or without the use of suitable organicsolvents, such as propylene glycol or polyethylene glycol. Dispersionsof the finely divided compounds can be made-up in aqueous starch orsodium carboxymethyl cellulose solution, or in suitable oil, such asarachis oil. These formulations can be sterilized by conventional, wellknown sterilization techniques. The formulations can containpharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike. The concentration of pyrrolo-napthyl acids in these formulationscan vary widely, and will be selected primarily based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the formulation can be a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation can also be a sterile injectablesolution or suspension in a nontoxic parenterally-acceptable diluent orsolvent, such as a solution of 1,3-butanediol. The formulations ofcommends can be presented in unit-dose or multi-dose sealed containers,such as ampules and vials.

Injection solutions and suspensions can be prepared, for example, fromsterile powders, granules, and tablets.

Compounds suitable for use in the practice of this invention can beadministered orally. The amount of a compound of the present inventionin the composition can vary widely depending on the type of composition,size of a unit dosage, kind of excipients, and other factors well knownto those of ordinary skill in the art. In general, the final compositioncan comprise from, for example, 0.000001 percent by weight (% w) to 10%w of the pyrrolo-napthyl acids, preferably 0.00001% w to 1% w, with theremainder being the excipient or excipients.

Pharmaceutical formulations for oral administration can be formulatedusing pharmaceutically acceptable carriers well known in the art indosages suitable for oral administration. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc. suitable for ingestion by thepatient. Formulations suitable for oral administration can consist of(a) liquid solutions, such as an effective amount of the packagednucleic acid suspended in diluents, such as water, saline or PEG 400;(b) capsules, sachets or tablets, each containing a predetermined amountof the active ingredient, as liquids, solids, granules or gelatin; (c)suspensions in an appropriate liquid; and (d) suitable emulsions.

Pharmaceutical preparations for oral use can be obtained throughcombination of the compounds of the present invention with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable additional compounds, ifdesired, to obtain tablets or dragee cores. Suitable solid excipientsare carbohydrate or protein fillers and include, but are not limited tosugars, including lactose, sucrose, mannitol, or sorbitol; starch fromcorn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents can be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof; such as sodium alginate. Tablet forms can include one or moreof lactose, sucrose, mannitol, sorbitol, calcium phosphates, cornstarch, potato starch, microcrystalline cellulose, gelatin, colloidalsilicon dioxide, talc, magnesium stearate, stearic acid, and otherexcipients, colorants, fillers, binders, diluents, buffering agents,moistening agents, preservatives, flavoring agents, dyes, disintegratingagents, and pharmaceutically compatible carriers. Lozenge forms cancomprise the active ingredient in a flavor, e.g., sucrose, as well aspastilles comprising the active ingredient in an inert base, such asgelatin and glycerin or sucrose and acacia emulsions, gels, and the likecontaining, in addition to the active ingredient, carriers known in theart

The compounds of the present invention can also be administered in theform of suppositories for rectal administration of the drug. Theseformulations can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

The compounds of the present invention can also be administered byintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995).

The compounds of the present invention can be administered in sustainedor controlled release dosage forms (e.g., employing a slow releasebioerodable delivery system), including depot injections, osmotic pumps(such as the Alzet implant made by Alza), pills, transdermal andtranscutaneous (including electrotransport) patches, and the like, forprolonged administration at a predetermined rate, preferably in unitdosage forms suitable for single administration of precise dosages. Thecompositions will typically include a conventional pharmaceuticalcarrier or excipient and a compound of the invention. In addition, thesecompositions can include other active agents, carriers, adjuvants, andthe like.

The compounds of the present invention can be delivered transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

Encapsulating materials can also be employed with the compounds of thepresent invention and the term “composition” is intended to include theactive ingredient in combination with an encapsulating material as aformulation, with or without other carriers. For example, the compoundsof the present invention can also be delivered as microspheres for slowrelease in the body. In one embodiment, microspheres can be administeredvia intradermal injection of drug, which slowly release subcutaneously(see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradableand injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months. Cachets can also beused in the delivery of the compounds of the present invention, e.g.,anti-atherosclerotic medicaments.

In another embodiment, the compounds of the present invention can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposome,or attached directly to the oligonucleotide, that bind to surfacemembrane protein receptors of the cell resulting in endocytosis. Byusing liposomes, particularly where the liposome surface carries ligandsspecific for target cells, or are otherwise preferentially directed to aspecific organ, one can focus the delivery of the compound into thetarget cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro,Am. J. Hosp. Pharm. 46:1576-1587, 1989).

In other cases, the preferred preparation can be a lyophilized powderin, for example, 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitolat a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

A pharmaceutical composition of the invention can optionally contain, inaddition to pyrrolo-napthyl acids, at least one other therapeutic agentuseful in the treatment of a disease or condition associated withincreased PAI-1 activity.

The pharmaceutical compositions are generally formulated as sterile,substantially isotonic and in full compliance with all GoodManufacturing Practice (GMP) regulations of the U.S. Food and DrugAdministration

E. Determining Dosage Regimens

For treatment purposes, the compositions or compounds disclosed hereincan be administered to the subject in a single bolus delivery, viacontinuous delivery (e.g., continuous transdermal, mucosal, orintravenous delivery) over an extended time period, or in a repeatedadministration protocol (e.g., by an hourly, daily or weekly, repeatedadministration protocol). The pharmaceutical formulations of the presentinvention can be administered, for example, one or more times daily, 3times per week, or weekly. In an exemplary embodiment of the presentinvention, the pharmaceutical formulations of the present invention areorally administered once or twice daily.

In this context, a therapeutically effective dosage of the biologicallyactive agent(s) can include repeated doses within a prolonged treatmentregimen that will yield clinically significant results to alleviate oneor more symptoms or detectable conditions associated with increasedPAI-1 activity. Determination of effective dosages in this context istypically based on animal model studies followed up by human clinicaltrials and is guided by determining effective dosages and administrationprotocols that significantly reduce the occurrence or severity oftargeted exposure symptoms or conditions in the subject. Suitable modelsin this regard include, for example, murine, rat, porcine, feline,non-human primate, and other accepted animal model subjects known in theart. Alternatively, effective dosages can be determined using in vitromodels (e.g., immunologic and histopathologic assays). Using suchmodels, only ordinary calculations and adjustments are typicallyrequired to determine an appropriate concentration and dose toadminister a therapeutically effective amount of the biologically activeagent(s) (e.g., amounts that are intranasally effective, transdermallyeffective, intravenously effective, or intramuscularly effective toelicit a desired response). In alternative embodiments, an “effectiveamount” or “therapeutically effective dose” of the biologically activeagent(s) will simply inhibit or enhance one or more selected biologicalactivity(ies) correlated with a disease or condition, as set forthabove, for either therapeutic or diagnostic purposes.

The actual dosage of biologically active agents will of course varyaccording to factors such as the extent of exposure and particularstatus of the subject (e.g., the subject's age, size, fitness, extent ofsymptoms, susceptibility factors, etc), time and route ofadministration, as well as other drugs or treatments being administeredconcurrently. Dosage regimens can be adjusted to provide an optimumprophylactic or therapeutic response. By “therapeutically effectivedose” herein is meant a dose that produces effects for which it isadministered. More specifically, a therapeutically effective dose of thecompound(s) of the invention preferably alleviates symptoms,complications, or biochemical indicia of diseases associated withincreased PAI-1 activity. The exact dose will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(Vols. 1-3, 1992); Lloyd, 1999, The Art, Science, and Technology ofPharmaceutical Compounding; and Pickar, 1999, Dosage Calculations). Atherapeutically effective dose is also one in which any toxic ordetrimental side effects of the active agent is outweighed in clinicalterms by therapeutically beneficial effects. It is to be further notedthat for each particular subject, specific dosage regimens should beevaluated and adjusted over time according to the individual need andprofessional judgment of the person administering or supervising theadministration of the compounds.

In an exemplary embodiment of the present invention, unit dosage formsof the compounds are prepared for standard administration regimens. Inthis way, the composition can be subdivided readily into smaller dosesat the physicians direction. For example, unit dosages can be made up inpacketed powders, vials or ampoules and preferably in capsule or tabletform. The active compound present in these unit dosage forms of thecomposition can be present in an amount of, for example, from about onegram to about fifteen grams or more, for single or multiple dailyadministration, according to the particular need of the patient. Byinitiating the treatment regimen with a minimal daily dose of about onegram, the blood levels of PAI-1 and the patients symptomatic reliefanalysis can be used to determine whether a larger or smaller dose isindicated. Effective administration of the compounds of this inventioncan be given at an oral dose of, for example, from about 0.1 mg/kg/dayto about 1,000 mg/kg/day. Preferably, administration will be from about10/mg/kg/day to about 600 mg/kg/day, more preferably from about 25 toabout 200 mg/kg/day, and even more preferably from about 50 mg/kg/day toabout 100 mg/kg/day. In some embodiments, a daily dosage of from about 1mg/kg to about 250 mg/kg is provided.

The compounds of the present invention can also be solvated, especiallyhydrated. Hydration can occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration can occur overtime due to the hygroscopic nature of the compounds.

In certain embodiments, the present invention is directed to prodrugs ofcompounds of formulas 1-5. The term “prodrug,” as used herein, means acompound that is convertible in vivo by metabolic means (e.g. byhydrolysis) to a compound of formulas 1-5. Various forms of prodrugs areknown in the art such as those discussed in, for example, Bundgaard,(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen,et al., (ed). “Design and Application of Prodrugs, Textbook of DrugDesign and Development, Chapter 5, 113-191 (1991), Bundgaard, et al.,Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. ofPharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella(eds.) Prodrugs as Novel Drug Delivery Systems, American ChemicalSociety (1975).

F. Kits

Pharmaceutical dosage forms comprising a compound of the presentinvention can be placed in an appropriate container and labeled fortreatment of a PAI-1 related disorder, e.g., leukemia. Additionally,another pharmaceutical comprising at least one other therapeutic agentuseful in the treatment of the PAI-1 related disorder can be placed inthe container as well and labeled for treatment of the indicateddisease. For administration of pharmaceutical dosage forms comprisingpyrrolo-napthyl acids, such labeling would include, for example,instructions concerning the amount, frequency and method ofadministration. Similarly, for administration of multiplepharmaceuticals provided in the container, such labeling would include,for example, instructions concerning the amount, frequency and method ofadministration of each dosage form.

EXAMPLES Example 1 Synthesis of3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acid

Step 1: 2-Bromo-1-(6-methoxy-2-naphthyl)ethanone Phenyltrimethylammoniuntribromide (9.45 g, 25.1 mmol) was added under nitrogen in portions overapproximately 2 h to a solution of1-(6-methoxy-naphthalen-2-yl)-ethanone (5.05 g, 25.2 mmol) in 50 mL ofanhydrous THF at room temperature. After the addition the reaction wasstirred at room temperature for 0.5 h. and then 250 mL of cold water wasadded. The solid present was collected by filtration, rinsed with 50 mLof water and dried under reduced pressure to give 6.66 g of a tan solid.Recrystallization of the solid from isopropyl alcohol gave2-bromo-1-(6-methoxy-2-naphthyl)ethanone (4.07 g, 58%) as a brown solid,mp 109-112° C. Elemental Analysis for C₁₃H₁₁BrO₂ Calc'd: C, 55.94; H,3.97; N, 0.00. Found: C, 56.03; H, 3.94; N, 0.00.

Step 2: Ethyl 2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate NaH(60%, 1.58 g, 35.8 mmol) was added under nitrogen in 4 equal portionsover a 30-minute period to a stirring solution of ethyl benzoylacetate(6.89 g, 35.8 mmol) in 100 mL of anhydrous DMF. After complete additionof the NaH, the mixture was allowed to stir under nitrogen at ambienttemperature for 1 hour. After 1 hour, a solution of2-bromo-1-(6-methoxy-2-naphthyl)ethanone (10.0 g, 35.8 mmol), preparedin the previous step, in 100 mL of anhydrous DMF was added dropwise viaa pressure-equalizing addition funnel. Total addition time wasapproximately 1.5 hours. By TLC analysis (25% EtOAc/Hexane), 30 minutesafter addition of the bromoketone was complete, there was no startingmaterial left. The reaction was slowly quenched by the addition of 1NHCl (250 mL). The precipitate was isolated by filtration, rinsed withwater and set aside, giving 8.58 g of product. The filtrate waspartitioned against EtOAc. The layers were separated and the aqueouslayer was extracted with two additional portions of EtOAc. The combinedextracts were washed five times with water, dried (MgSO₄), filtered andthe solvent removed under reduced pressure to give a crude yellow solid.Dissolution of the solid in a minimal amount of methylene chloridefollowed by precipitation of a solid by the addition of a 2× volume ofEtOAc afforded 3.34 g of a white powder. Combination of the like batchesgave ethyl 2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate (11.92 g,85.2%) as an off-white powder, mp 136-137° C. Elemental Analysis forC₂₄H₂₂O₅ Calc'd: C, 73.83; H, 5.68; N, 0.00. Found: C, 73.11; H, 5.75;N, 0.00.

Step 3: 1-(6-Methoxy-2-naphthyl)-4-phenylbutane-1,4-dione. Ethyl2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate (5.00 g, 12.8 mmol),prepared in the previous step, was dissolved in 300 mL oftetrahydrofuran. After complete dissolution of the ester, 1N NaOHsolution (28.2 mL, 28.2 mmol) was added to the THF solution. The mixturewas heated to gentle reflux for 24 hours, then allowed to cool back toambient temperature. The mixture was acidified with 1N hydrochloric acid(105 mL) and allowed to stir for 15 minutes. The THF was then removedunder reduced pressure and the residue was partitioned between methylenechloride and 1N HCl. The layers were separated, and the aqueous layerwas extracted two times with methylene chloride. The combined extractswere dried (MgSO₄), filtered and the solvent removed under reducedpressure. Purification on silica gel (300 g, 200-300 mesh) usingmethylene chloride as the eluent gave1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione as a white solid (1.64g, 40%), mp 163.5-164.5° C. Elemental Analysis for C₂₁H₁₈O₃ Calc'd: C,79.23; H, 5.70; N, 0.00. Found: C, 79.25; H, 5.70; N, 0.00

Step 4: 2-(6-Methoxy-2-naphthyl)-5-phenyl-1H-pyrrole. A mixture of1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.00 g, 3.14 mmol),prepared in the previous step, ammonium acetate (12.1 g, 157 mmol) andacetic acid (100 mL) was heated to 100° C. under a nitrogen atmospherefor three hours. The mixture was cooled to ambient temperature, and theprecipitate was isolated by filtration to give2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid (0.86 g,91%), mp 208.5-209.5° C. Elemental Analysis for C₂₁H₁₇NO Calc'd: C,84.25; H, 5.72; N, 4.68. Found: C, 84.25; H, 5.77; N, 4.56.

Step 5: 6-(5-Phenyl-1H-pyrrol-2-yl)-2-naphthol. A mixture of2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole (0.72 g, 2.4 mmol),prepared in the previous step, and pyridine hydrochloride (7.2 g) washeated at 200° C. under a nitrogen atmosphere for 1 hour. The mixturewas cooled to ambient temperature and the solids were dissolved in 1NHCl (150 mL). The mixture was extracted three times with methylenechloride. The combined extracts were washed one time with water, dried(MgSO₄), filtered and the solvent removed under reduced pressure to give6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol as a grayish solid (0.65 g, 95%),mp 209.5-210.5° C. Elemental Analysis for C₂₀H₁₅NO Calc'd: C, 84.19; H,5.30; N, 4.91. Found: C, 83.38; H, 5.38; N, 4.67.

Step 6: Methyl3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate. Amixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.05 mmol),prepared in the previous step,3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.492g, 1.58 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in acetone (50mL) was stirred under nitrogen at ambient temperature overnight. Theacetone was removed under reduced pressure and the residue partitionedbetween EtOAc and water. The layers were separated and the aqueous layerwas extracted two times with EtOAc. The combined extracts were dried(MgSO₄), filtered and the solvent removed under reduced pressure.Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40Lcolumn (120 g Silica Gel, 60 Å) using 25% to 60% methylene chloride inhexane as the eluent gave methyl3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate as agrayish solid (0.447 g, 95%), mp 140-141° C. Elemental Analysis forC₃₀H₂₅NO₃ Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 80.26; H, 5.70;N, 2.94.

Step 7:3-Phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acid.A mixture of methyl3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate (0.25g, 0.56 mmol), prepared in the previous step, and 1N NaOH (1.1 mL, 1.1mmol) in THF (25 mL) was stirred under nitrogen at ambient temperatureovernight. By TLC analysis, starting material was still present. Themixture was heated to 60° C. for two hours, at which time no startingmaterial remained. The mixture was cooled to ambient temperature,acidified with 1N HCl (2 mL) and the volatiles were removed underreduced pressure (without the application of heat). The residue wasslurried with water, the solids filtered and washed with water. Thesolids were dissolved in methylene chloride, the solution dried (MgSO₄),filtered and the solvent removed under reduced pressure to give thetitle compound as an off-white solid (0.22 g, 90%), mp 176-178° C.Elemental Analysis for C₂₉H₂₃NO₃ Calc'd: C, 80.35; H, 5.35; N, 3.23.Found: C, 79.19; H, 5.31; N, 2.97.

Example 2 Synthesis of2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid

Step 1: 1-Benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole. In asimilar manner as described in step 4 of Example 1, the title compoundwas prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione(0.300 g, 0.942 mmol), prepared in step 3 of Example 1, and benzyl amine(0.121 g, 1.13 mmol). The crude material was dissolved in methylenechloride and filtered through silica gel (95 g, 200-300 mesh). Thesolvent was removed under reduced pressure to give1-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid(0.32 g, 87%), mp 152-153° C. Elemental Analysis for C₂₈H₂₃NO Calc'd: C,86.34; H, 5.95; N, 3.60. Found: C, 85.46; H, 6.06; N, 3.58.

Step 2: 6-(1-Benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol. In a similarmanner as described in step 5 of Example 1, the title compound wasprepared from 1-benzyl-2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole(0.22 g, 0.56 mmol), prepared in the previous step, and pyridinehydrochloride (15 g) heated to 180° C. under nitrogen for 3 hours.Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+Mcolumn (90 g Silica Gel, 60 Å) using methylene chloride as the eluentgave 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol a grayish solid(0.155 g, 73%), mp 153-154° C. Elemental Analysis for C₂₇H₂₁NO Calc'd:C, 86.37; H, 5.64; N, 3.73. Found: C, 85.95; H, 5.86; N, 3.59.

Step 3: Methyl2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate.In a similar manner as described in step 6 of Example 1, the titlecompound was prepared from6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.140 g, 0.373 mmol),prepared in the previous step,3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.175g, 0.560 mmol) and cesium carbonate (0.243 g, 0.746 mmol). Purificationon a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 gSilica Gel, 60 Å) using 20% to 50% methylene chloride in hexane as theeluent gave methyl2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoateas a white solid (0.175 g, 88%), mp 57-62° C. Elemental Analysis forC₃₇H₃₁NO₃ Calc'd: C, 82.66; H, 5.81; N, 2.61. Found: C, 82.39; H, 5.88;N, 2.46.

Step 4:2-{[6-(1-Benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid. In a similar manner as described in step 7 of Example 1, the titlecompound was prepared from methyl2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate(0.145 g, 0.270 mmol), prepared in the previous step, and the additionof water (3 mL) to the reaction mixture. After the volatiles wereremoved under reduced pressure, the residue was partitioned betweenwater and methylene chloride. The layers were separated and the aqueouslayer was extracted one time with methylene chloride. The combinedextracts were dried (MgSO₄), filtered and the solvent removed underreduced pressure to give the title compound as an off-white solid (0.127g, 90%), mp 70-80° C. Elemental Analysis for C₃₆H₂₉NO₃.0.48H₂O Calc'd:C, 81.23; H, 5.67; N, 2.63. Found: C, 80.67; H, 6.28; N, 2.36.

Example 3 Synthesis of5-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole

Step 1: {[6-(5-Phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile. In asimilar manner as described in step 6 of Example 1, the title compoundwas prepared from 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.285 g, 1.00mmol), prepared in step 5 of Example 1, bromoacetonitrile (0.144 g, 1.20mmol) and cesium carbonate (1.63 g, 5.00 mmol) with the exception thatthe reaction was complete after 2 hours at ambient temperature. Theisolated tan solids (0.323 g, 100%) were used without furtherpurification, mp 141.5-142.5° C. Elemental Analysis for C₂₂H₁₆N₂OCalc'd: C, 81.46; H, 4.97; N, 8.64. Found: C, 80.37; H, 4.93; N, 8.57.

Step 2:5-({[6-(5-Phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole. Amixture of {[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile(0.20 g, 0.62 mmol), prepared in the previous step, ammonium chloride(0.12 g, 1.85 mmol) and sodium azide (0.099 g, 1.85 mmol) in DMF (10 mL)was heated at 100° C. under nitrogen for 5 hours. After cooling toambient temperature, TLC analysis showed that starting materialremained. An additional portion each of ammonium chloride and sodiumazide was added, and the mixture was again heated at 100° C. for 4hours, at which time no starting material remained. The mixture wascooled to ambient temperature, acidified with 1N HCl (5 mL) and dilutedwith water (20 mL). The precipitated solids were isolated by vacuumfiltration to give the title compound as a gray solid (0.202 g, 89%), mp237-240° C. (dec). Elemental Analysis for C₂₂H₁₇N₅O.0.55H₂O.0.11 C₃H₇NOCalc'd: C, 69.60; H, 4.94; N, 18.57. Found: C, 69.71; H, 4.64; N, 18.61.

Example 4 Synthesis of5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole

Step 1:{[6-(1-Benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile. In asimilar manner as described in step 1 of Example 3, the title compoundwas prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250g, 0.665 mmol), prepared in step 2 of Example 2, bromoacetonitrile(0.096 g, 0.80 mmol) and cesium carbonate (1.08 g, 3.33 mmol) with theexception that the reaction was complete after 70 minutes at ambienttemperature. The crude material was dissolved in methylene chloride andfiltered through silica gel (45 g, 200-300 mesh). The solvent wasremoved under reduced pressure to give{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as abeige solid (0.276 g, 100%), mp 156-157° C. Elemental Analysis forC₂₉H₂₂N₂O Calc'd: C, 84.03; H, 5.35; N, 6.76. Found: C, 83.15; H, 5.46;N, 6.54.

Step 2:5-({[6-(1-Benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole.In a similar manner as described in step 2 of Example 3, the titlecompound was prepared from{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20g, 0.48 mmol), prepared in the previous step, ammonium chloride (0.077g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). Thesolids were isolated by vacuum filtration and dissolved in methylenechloride. The organic solution was dried (MgSO₄), filtered and thesolvent removed under reduced pressure to give5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleas an amorphous beige solid (0.203 g, 92%), mp 190-200° C. (dec).Elemental Analysis for C₂₉H₂₃N₅O.0.49H₂O.0.21 C₃H₇NO Calc'd: C, 73.90;H, 5.32; N, 15.15. Found: C, 73.05; H, 5.25; N, 15.03.

Example 5 Synthesis of5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole

Step 1: 2-(6-Methoxy-2-naphthyl)-1-methyl-5-phenyl-1H-pyrrole. In asimilar manner as described in step 4 of Example 1, the title compoundwas prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione(3.00 g, 9.42 mmol), prepared in step 3 of Example 1, and methyl amine(8 M solution in EtOH, 100 mL, 800 mmol). Isolation of the solids byvacuum filtration gave2-(6-methoxy-2-naphthyl)-1-methyl-5-phenyl-1H-pyrrole as a white solid(2.5 g, 85%), mp 197-198° C. Elemental Analysis for C₂₂H₁₉NO Calc'd: C,84.31; H, 6.11; N, 4.47. Found: C, 84.47; H, 6.08; N, 4.41.

Step 2: 6-(1-Methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol. In a similarmanner as described in step 5 of Example 1, the title compound wasprepared from 2-(6-methoxy-2-naphthyl)-1-methyl-5-phenyl-1H-pyrrole (2.3g, 7.3 mmol), prepared in the previous step, and pyridine hydrochloride(60 g) heated at 200° C. for 3 hours under a nitrogen atmosphere. Thecrude material was dissolved in EtOAc and filtered through silica gel(95 g, 200-300 mesh). The solvent was removed under reduced pressure togive 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol as a tan solid (2.0g, 91%), mp 230-231° C. Elemental Analysis for C₂₁H₁₇NO. Calc'd: C,84.25; H, 5.72; N, 4.68. Found: C, 84.24; H, 5.76; N, 4.61.

Step 3:{[6-(1-Methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile. In asimilar manner as described in step 1 of Example 4, the title compoundwas prepared from 6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.45g, 1.5 mmol), prepared in the previous step, bromoacetonitrile (0.216 g,1.8 mmol) and cesium carbonate (2.45 g, 7.52 mmol) with the exceptionthat the reaction was complete after 100 minutes at ambient temperature.The crude material was dissolved in methylene chloride and filteredthrough silica gel (45 g, 200-300 mesh). The solvent was removed underreduced pressure to give{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as anoff-white solid (0.494 g, 97%), mp 191.5-192.5° C. Elemental Analysisfor C₂₃H₁₈N₂O Calc'd: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.06; H,5.14; N, 8.04.

Step 4:5-({[6-(1-Methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole.In a similar manner as described in step 2 of Example 3, the titlecompound was prepared from{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20g, 0.48 mmol), prepared in the previous step, ammonium chloride (0.077g, 1.44 mmol) and sodium azide (0.094 g, 1.44 mmol) in DMF (10 mL). Theprecipitated solids were isolated by vacuum filtration to give5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleas a white solid (0.228 g, 81%), mp 231-233° C. (dec). ElementalAnalysis for C₂₃H₁₉N₅O.0.34H₂O.0.07 C₃H₇NO Calc'd: C, 70.99; H, 5.18; N,18.08. Found: C, 70.84; H, 5.07;N, 18.18.

Example 6 Synthesis of{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid

Step 1: Methyl{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate. In asimilar manner as described in step 1 of Example 4, the title compoundwas prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250g, 0.665 mmol), prepared in step 2 of Example 2, methyl bromoacetate(0.122 g, 0.797 mmol) and cesium carbonate (1.08 g, 3.33 mmol). Theisolated tan amorphous solid (0.298 g, 100%) was used without furtherpurification, mp 101-102° C. Elemental Analysis for C₃₀H₂₅NO₃ Calc'd: C,80.51; H, 5.63; N, 3.13. Found: C, 79.81; H, 5.60; N, 2.83.

Step 2: {[6-(1-Benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}aceticacid. A mixture of methyl{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.250 g,0.559 mmol), prepared in the previous step, and 1N NaOH (0.84 mL, 0.84mmol) in 1:1:1 THF:MeOH:water (30 mL) was stirred at ambient temperaturefor 10 minutes. The volatiles were removed under reduced pressure(without the application of heat). The residue was partitioned between0.1N HCl and EtOAc. The layers were separated and the aqueous layer wasextracted one time with EtOAc. The combined extracts were dried (MgSO₄),filtered and the solvent removed under reduced pressure to give thetitle compound as a pale-yellow solid (0.23 g, 95%), mp 171-172° C.Elemental Analysis for C₂₉H₂₃NO₃.0.17H₂O Calc'd: C, 79.79; H, 5.39; N,3.21. Found: C, 79.88; H, 5.37; N, 2.96.

Example 7 Synthesis of2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid

Step 1: Methyl2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate.In a similar manner as described in step 6 of Example 1, the titlecompound was prepared from6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.00 mmol),prepared in step 2 of Example 5,3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.469g, 1.50 mmol) and cesium carbonate (0.653 g, 2.00 mmol) with theexception that this reaction was complete after 4 hours at ambienttemperature. Purification on a Biotage Horizon™ system with a KP-SilFlash 40+M column (100 g Silica Gel, 60 Å) using 25% to 55% methylenechloride in hexane as the eluent gave methyl2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoateas a white solid (0.437 g, 94%), mp 117-118° C. Elemental Analysis forC₃₁H₂₇NO₃ Calc'd: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.35; H, 6.16;N, 2.91.

Step 2:2-{[6-(1-Methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid. In a similar manner as described in step 2 of Example 6, the titlecompound was prepared from methyl2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate(0.200 g, 0.433 mmol), prepared in the previous step, and 1N NaOH (0.65mL, 0.65 mmol) in 1.5:1.5:1 THF:MeOH:water (40 mL) with the exceptionthat this reaction was complete after 18 hours (overnight) at ambienttemperature. The title compound was isolated as a pale-yellow solid(0.194 g, 100%) and used without further purification, mp 171-173° C.Elemental Analysis for C₃₀H₂₅NO₃.0.05H₂O Calc'd: C, 80.35; H, 5.64; N,3.12. Found: C, 80.38; H, 5.67; N, 3.00.

Example 8 Synthesis of3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid

Step 1:2-(6-Methoxy-2-naphthyl)-5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrole.In a similar manner as described in step 4 of Example 1, the titlecompound was prepared from1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (0.300 g, 0.942 mmol),prepared in step 3 of Example 1, and trifluoromethylbenzyl amine (0.121g, 1.13 mmol) with the exception that this reaction required 4 hours ofheating at 125° C. The crude material was isolated by removal of theacetic acid under reduced pressure. The crude material was dissolved in50% methylene chloride in hexane and filtered through silica gel (45 g,200-300 mesh). The solvent was removed under reduced pressure to give2-(6-methoxy-2-naphthyl)-5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrroleas an off-white amorphous solid (2.4 g, 83%), mp 94-97° C. ElementalAnalysis for C₂₉H₂₂F₃NO Calc'd: C, 76.14; H, 4.85; N, 3.06. Found: C,76.56; H, 5.58; N, 2.82.

Step 2:6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol. Ina similar manner as described in step 5 of Example 1, the title compoundwas prepared from2-(6-methoxy-2-naphthyl)-5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrole(0.70 g, 1.5 mmol), prepared in the previous step, and pyridinehydrochloride (7 g) heated to 165° C. under nitrogen for 12 hours.Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+Mcolumn (100 g Silica Gel, 60 Å) using 50% to 90% methylene chloride inhexane as the eluent gave6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol asa reddish-brown amorphous solid (0.52 g, 77%), mp 63-66° C. ElementalAnalysis for C₂₈H₂₀F₃NO Calc'd: C, 75.84; H, 4.55; N, 3.16. Found: C,75.18; H, 4.41; N, 3.13.

Step 3: Methyl3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoate.In a similar manner as described in step 1 of Example 7, the titlecompound was prepared from6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol(0.300 g, 0.676 mmol), prepared in the previous step,3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.317g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol). Purification ona Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g SilicaGel, 60 Å) using 25% to 65% methylene chloride in hexane as the eluentgave methyl3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoateas an off-white amorphous solid (0.367 g, 90%), mp 50-55° C. ElementalAnalysis for C₃₈H₃₀F₃NO₃ Calc'd: C, 75.36; H, 4.99; N, 2.31. Found: C,75.24; H, 5.16; N, 2.22.

Step 4:3-Phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid. In a similar manner as described in step 2 of Example 6, the titlecompound was prepared from methyl3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoate(0.200 g, 0.330 mmol), prepared in the previous step, and 1N NaOH (0.50mL, 0.50 mmol) in 1.33:1.33:1 THF:MeOH:water (33 mL) with the exceptionthat this reaction was not complete after 18 hours (overnight) atambient temperature. The reaction was warmed to 30° C. for 1.5 hours, anadditional portion of 1N NaOH (0.50 mL, 0.50 mmol) was added and themixture maintained at 30° C. for an additional 1.5 hours. The isolatedyellow amorphous solid was purified by reverse-phase (C18) HPLC using20% water in acetonitrile with 0.1% formic acid as the eluent. Isolationof the product from the chromatography fractions gave3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid as a greenish amorphous solid (0.139 g, 71%), mp 153-155° C.Elemental Analysis for C₃₇H₂₈F₃NO₃.0.24H₂O.0.10 C₆H₁₄Calc'd: C, 74.70;H, 4.98; N, 2.32. Found: C, 74.67; H, 5.23; N, 2.25.

Example 9 Synthesis of5-{[(6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazole

Step 1:[(6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetonitrile.In a similar manner as described in step 1 of Example 3, the titlecompound was prepared from6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol(0.250 g, 0.564 mmol), prepared in step 2 of Example 8,bromoacetonitrile (0.081 g, 0.68 mmol) and cesium carbonate (0.920 g,2.82 mmol). Purification on a Biotage FlashElute™system with a KP-SilFlash 40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloridein hexane as the eluent gave[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetonitrileas a white solid (0.251 g, 92%), mp 154-155° C. Elemental Analysis forC₃₀H₂₁F₃N₂O.0.10 CH₂Cl₂ Calc'd: C, 73.65; H, 4.35; N, 5.71. Found: C,73.58; H, 4.46; N, 5.64.

Step 2:5-{[(6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazole.In a similar manner as described in step 2 of Example 3, the titlecompound was prepared from[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetonitrile(0.180 g, 0.373 mmol), prepared in the previous step, ammonium chloride(0.060 g, 1.12 mmol) and sodium azide (0.073 g, 1.12 mmol) in DMF (10mL). The reaction mixture was acidified with 1N HCl (7 mL) andpartitioned against methylene chloride. The layers were separated andthe aqueous layer was extracted three times with methylene chloride. Thecombined extracts were dried (MgSO₄), filtered and the solvent removedunder reduced pressure to give an oil. The oil contained a large amountof DMF, so it was dissolved in EtOAc and partitioned against water. Theorganic layer was washed 5 times with water, dried (MgSO₄), filtered andthe solvent removed under reduced pressure. The crude material wasdissolved in methylene chloride and filtered through silica gel (95 g,200-300 mesh). The silica gel was rinsed with one portion (500 mL) ofmethylene chloride and then five portions (100 mL each) of 50% methylenechloride in hexane with 1% formic acid. The filtrate portions thatcontained clean product were combined and the solvent was removed underreduced pressure to give5-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazoleas an off-white solid (0.169 g, 86%), mp 173-175° C. Elemental Analysisfor C₃₀H₂₂F₃N₅O.0.15H₂O Calc'd: C, 68.21; H, 4.26; N, 13.26. Found: C,68.38; H, 4.03; N, 13.22.

Example 10 Synthesis of[(6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]aceticacid

Step 1: Methyl[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate.In a similar manner as described in step 1 of Example 3, the titlecompound was prepared from6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol(0.250 g, 0.564 mmol), prepared in step 2 of Example 8, methylbromoacetate (0.103 g, 0.676 mmol) and cesium carbonate (0.920 g, 2.82mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloride inhexane as the eluent gave methyl[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetateas an off-white solid (0.271 g, 93%), mp 90-91° C. Elemental Analysisfor C₃₁H₂₄F₃NO₃.0.09 C₆H₁₄Calc'd: C, 72.39; H, 4.87; N, 2.68. Found: C,72.26; H, 4.68; N, 2.28.

Step 2:[(6-{5-Phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]aceticacid. In a similar manner as described in step 2 of Example 6, the titlecompound was prepared from methyl[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate(0.20 g, 0.38 mmol), prepared in the previous step, and 1N NaOH (0.58mL, 0.58 mmol) in 1.67:1.67:1 THF:MeOH:water (39 mL). Purification on aBiotage Horizon™ system with a KP-Sil Flash 25+M column (40 g SilicaGel, 60 Å) using 25% EtOAc in hexane with 1% formic acid as the eluentgave[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]aceticacid as an off-white solid (0.155 g, 79%), mp 154-156° C. ElementalAnalysis for C₃₀H₂₂F₃NO₃.0.02H₂O Calc'd: C, 71.80; H, 4.43; N, 2.79.Found: C, 71.96; H, 4.55; N, 2.61.

Example 11 Synthesis of5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole

Step 1: 2-(6-Methoxy-2-naphthyl)-1,5-diphenyl-1H-pyrrole. In a similarmanner as described in step 1 of Example 8, the title compound wasprepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.50 g,4.71 mmol), prepared in step 3 of Example 1, and aniline (3.07 g, 33.0mmol). Purification on silica gel (500 g, 200-300 mesh) using 0% to 50%methylene chloride in hexane as the eluent gave2-(6-methoxy-2-naphthyl)-1,5-diphenyl-1H-pyrrole as an off-white solid(1.36 g, 77%), mp 199-200° C. Elemental Analysis for C₂₇H₂₁NO.0.11CH₂Cl₂ Calc'd: C, 84.62; H, 5.56; N, 3.64. Found: C, 84.55; H, 5.67; N,3.61.

Step 2: 6-(1,5-Diphenyl-1H-pyrrol-2-yl)-2-naphthol. In a similar manneras described in step 5 of Example 1, the title compound was preparedfrom 2-(6-methoxy-2-naphthyl)-1,5-diphenyl-1H-pyrrole (1.25 g, 3.33mmol), prepared in the previous step, and pyridine hydrochloride (30 g)with the exception that this reaction required heating at 205° C.Purification on silica gel (500 g, 200-300 mesh) using methylenechloride as the eluent gave 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphtholas a reddish solid (1.00 g, 83%), mp 222-223° C. Elemental Analysis forC₂₆H₁₉NO.0.11 C₄H₈O₂ Calc'd: C, 85.57; H, 5.40; N, 3.77. Found: C,85.28; H, 5.53; N, 3.73.

Step 3: {[6-(1,5-Diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile.In a similar manner as described in step 6 of Example 1, the titlecompound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol(0.200 g, 0.553 mmol), bromoacetonitrile (0.0796 g, 0.664 mmol) andcesium carbonate (0.900 g, 2.77 mmol) with the exception that theproduct was extracted with two portions each of methylene chloride andEtOAc. Purification on a Biotage Horizon™ system with a KP-Sil Flash40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloridein hexane as the eluent gave{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as a whitesolid (0.170 g, 77%), mp 229-230° C. Elemental Analysis forC₂₈H₂₀N₂O.0.05 CH₂Cl₂ Calc'd: C, 83.24; H, 5.01; N, 6.92. Found: C,83.12; H, 4.77; N, 6.89.

Step 4:5-({[6-(1,5-Diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole.In a similar manner as described in step 2 of Example 3, the titlecompound was prepared from{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.180 g,0.373 mmol), prepared in the previous step, ammonium chloride (0.060 g,1.12 mmol) and sodium azide (0.073 g, 1.12 mmol) in DMF (10 mL). Theprecipitated solids were isolated by vacuum filtration to give5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleas an off-white solid (0.130 g, 98%), mp 269-270° C. (dec). ElementalAnalysis for C₂₈H₂₁N₅O Calc'd: C, 75.83; H, 4.77; N, 15.79. Found: C,75.83; H, 4.69; N, 15.50.

Example 12 Synthesis of{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid

Step 1: Methyl {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate.In a similar manner as described in step 6 of Example 1, the titlecompound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol(0.200 g, 0.553 mmol), prepared in step 2 of Example 11, methylbromoacetate (0.102 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77mmol) with the exception that the product was extracted with methylenechloride. Purification on a Biotage Horizon™ system with a KP-Sil Flash40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloridein hexane as the eluent gave methyl{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate as an off-whitesolid (0.22 g, 92%), mp 188-189° C. Elemental Analysis forC₂₉H₂₃NO₃.0.16 CH₂Cl₂ Calc'd: C, 78.34; H, 5.26; N, 3.13. Found: C,77.73; H, 5.08; N, 3.07.

Step 2: {[6-(1,5-Diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid. Ina similar manner as described in step 2 of Example 6, the title compoundwas prepared from methyl{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.17 g, 0.39mmol), prepared in the previous step, and 1N NaOH (0.59 mL, 0.59 mmol)in 5:5:1 THF:MeOH:water (55 mL) with the exception that this reactionrequired heating to 65° C. and was complete after 6 hours. The stillwarm reaction mixture was filtered and then allowed to cool to ambienttemperature. The mixture was acidified with 1N HCl (2.5 mL) and thevolatiles were removed under reduced pressure (without the addition ofheat). The resulting slurry was diluted with water (25 mL) and thesolids were isolated by filtration to give{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid as anoff-white solid (0.148 g, 90%), mp 258-260° C. (dec). Elemental Analysisfor C₂₈H₂₁NO₃.0.23H₂O Calc'd: C, 79.39; H, 5.11; N, 3.31. Found: C,78.84; H, 5.03; N, 3.00.

Example 13 Synthesis of2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid

Step 1: Methyl2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate.In a similar manner as described in step 1 of Example 7, the titlecompound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol(0.300 g, 0.676 mmol), prepared in step 2 of Example 11,3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.317g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol) with theexception that this reaction was complete after 30 minutes at ambienttemperature. Purification on a Biotage Horizon™ system with a KP-SilFlash 25+M column (40 g Silica Gel, 60 Å) using 25% to 65% methylenechloride in hexane as the eluent gave methyl2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoateas a white solid (0.257 g, 89%), mp 178-179° C. Elemental Analysis forC₃₆H₂₉NO₃ Calc'd: C, 82.58; H, 5.58; N, 2.67. Found: C, 81.87; H, 5.10;N, 2.50.

Step 2:2-{[6-(1,5-Diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid. In a similar manner as described in step 2 of Example 12, thetitle compound was prepared from methyl2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate(0.186 g, 0.355 mmol), prepared in the previous step, and 1N NaOH (0.53mL, 0.53 mmol) in 2:2:1 THF:MeOH:water (25 mL). The starting materialrequired heating to dissolve in the THF (10 mL). After the solution wasclear, MeOH (10 mL) was added followed by the water (5 mL). The reactionwas complete after 2.5 hours. The solids were isolated by filtration togive2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid as a beige solid (0.17 g, 94%), mp 194-196° C. (dec). ElementalAnalysis for C₃₅H₂₇NO₃.0.23H₂O Calc'd: C, 81.83; H, 5.39; N, 2.73.Found: C, 81.07; H, 5.44; N, 2.56.

Example 144-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoicacid

Step 1: methyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate.A mixture of6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol(250 mg, 0.564 mmol), prepared in step 2 of Example 8, methyl4-(bromomethyl)benzoate (155 mg, 0.677 mmol) and cesium carbonate (918mg, 2.82 mmol) in 50 mL of acetone was stirred under nitrogen at roomtemperature for 1.5 h. The reaction was concentrated under reducedpressure to remove the acetone. The residue was partitioned betweenethyl acetate and water. The aqueous layer was separated and extractedmultiple times with ethyl acetate. The combined extracts were dried(MgSO₄), filtered and the solvent removed under reduced pressure to give0.36 g of a tan solid. Purification of the solid on a Biotage Horizon™system with a KP-SIL Flash 40+M column using 50% methylene in hexane asthe eluent gave methyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate(260 mg, 78%) as an off-white solid, mp 154-155° C. Elemental Analysisfor C₃₇H₂₈F₃NO₃ Calc'd: C, 75.12; H, 4.77; N, 2.37. Found: C, 75.15; H,4.63; N, 2.30.

Step 2:4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoicacid. A mixture of methyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate(200 mg, 0.338 mmol), prepared in the previous step, and 1 N NaOH (507μL, 0.507 mmol) in 20 mL of THF plus 20 mL of methanol plus 5 mL waterwas refluxed under nitrogen for 9 h. The reaction was filtered and thenallowed to cool to room temperature. The reaction was acidified by theaddition of 2.5 mL of 1 N HCl and then concentrated under reducedpressure to remove the THF and methanol. The residue was diluted withwater. The solid formed was collected by filtration, rinsed with waterand dried under reduced pressure to give the title compound (186 mg,95%) as an off-white solid, mp 228-229° C. Elemental Analysis forC₃₆H₂₆F₃NO₃.0.15H₂O.0.04 C₄H₈O Calc'd: C, 74.47; H, 4.60; N, 2.40.Found: C, 74.52; H, 4.49; N, 2.68.

Example 154-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acid

Step 1: Methyl4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate. Amixture of 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (300 mg, 0.830mmol), prepared in step 2 of Example 11, methyl 4-(bromomethyl)benzoate(228 mg, 996 mmol) and cesium carbonate (1.38 g, 4.15 mmol) in 50 mL ofacetone was stirred under nitrogen at room temperature for 2.5 h. Thereaction was concentrated under reduced pressure to remove the acetone.The residue was partitioned between methylene chloride and water. Theaqueous layer was separated and extracted two times with methylenechloride. The combined extracts were dried (MgSO₄) filtered and thesolvent removed under reduced pressure to give 486 mg of a tan solid.Purification of the solid on a Biotage Horizon™ system with a KP-SILFlash 40+M column using 10% to 50% methylene chloride in hexane as theeluent gave methyl4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate (320mg, 76%) as a very light red solid, mp 218-219° C. Elemental analysisfor C₃₅H₂₇NO₃ Calc'd: C, 82.49; H, 5.34; N, 2.75. Found: C, 81.71; H,5.23; N, 2.64.

Step 2:4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acid.A mixture of methyl4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoate (235mg, 0.461 mmol), prepared in the previous step, and 1 N NaOH (692 μL,0.692 mmol) in 30 mL of THF plus 30 mL of methanol plus 5 mL of waterwas refluxed under nitrogen for 7 h. The reaction was filtered, cooledto room temperature, acidified by the addition of 2.5 mL of 1 N HCl andthen concentrated under reduced pressure to remove the THF and methanol.The solid present was collected by filtration, rinsed with water anddried under reduced pressure to give the title compound (225 mg, 99%) asa white solid, mp 309-310° C. Elemental Analysis for C₃₄H₂₅NO₃.0.05C₄H₈O.0.19H₂O Calc'd: C, 81.73; H, 5.17; N, 2.79. Found: C, 81.94; H,5.02; N, 2.65.

Example 164-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalicacid

Step 1: Dimethyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate.A mixture of6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol(200 mg, 0.451 mmol), prepared in step 2 of Example 8, dimethyl4-(bromomethyl)isophthalate (155 mg, 0.541 mmol) and cesium carbonate(734 mg, 2.25 mmol) in 40 mL of acetone was stirred under nitrogen atroom temperature for 1.5 h. The reaction was concentrated under reducedpressure to remove the acetone. The residue was partitioned betweenmethylene chloride and water. The aqueous layer was separated andextracted two times with methylene chloride. The combined extracts weredried (MgSO₄), filtered and the solvent removed under reduced pressureto give 312 mg of a yellow solid. Purification of the solid on a BiotageHorizon™ system with a KP-SIL Flash 40+M column using methylene chloridein hexane to as the eluent gave dimethyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate(200 mg, 68%) as an off-white solid, mp 172-174° C. Elemental analysisfor C₃₉H₃₀F₃NO₅ Calc'd: C, 72.10; H, 4.65; N, 2.16. Found: C, 71.47; H,4.22; N, 2.16.

Step 2:4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalicacid. A mixture of dimethyl4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalate(165 mg, 0.254 mmol), prepared in the previous step, and 1 N NaOH (1.52mL, 1.52 mmol) in 30 mL of THF plus 20 mL of methanol plus 5 mL of waterwas refluxed under nitrogen for 6 h. The reaction was filtered, cooledto room temperature, acidified by the addition of 5 mL of 1 N HCl andthen concentrated under reduced pressure to remove the THF and methanol.The solid present was collected by filtration, rinsed with water anddried under reduced pressure at 60° C. to give the title compound (148mg, 94%) as a yellow solid, mp 250-252° C. Elemental Analysis forC₃₇H₂₆F₃NO₅.0.18 C₄H₈O.0.34H₂O Calc'd: C, 70.71; H, 4.42; N, 2.19.Found: C, 70.65; H, 4.34; N, 2.13.

Example 174-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acid

Step 1: Dimethyl4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate. Amixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (200 mg, 0.701 mmol),prepared in step 5 of Example 1, dimethyl 4-(bromomethyl)isophthalate(241 mg, 0.841 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in 50 mLof acetone was stirred at room temperature for 1.5 h. The reaction wasconcentrated under reduced pressure to remove the acetone. The residuewas partitioned between methylene chloride and water. The aqueous layerwas separated and extracted two times with methylene chloride. Thecombined extracts were dried (MgSO₄), filtered and the solvent removedunder reduced pressure to give a yellow solid. Purification of the solidon a Biotage Horizon™ system with a KP-SIL Flash 40+M column using agradient of 85% methylene chloride in hexane to 100% methylene chlorideas the eluent gave dimethyl4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (280mg, 81%) as a yellow solid, mp 203-205° C. Elemental Analysis forC₃₁H₂₅NO₅.0.10 CH₂Cl₂ Calc'd: C, 74.70; H, 5.08; N, 2.80. Found: C,74.24; H, 4.80; N, 2.76.

Step 2:4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acid:A mixture of dimethyl4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalate (230mg, 0.468 mmol), prepared in the previous step, and 1 N NaOH (2.81 mL,2.81 mmol) in 30 mL of THF plus 20 mL of methanol plus 5 mL of water wasrefluxed under nitrogen for 7 h. The reaction was filtered, cooled toroom temperature, acidified by the addition of 5 mL of 1 N HCl and thenconcentrated under reduced pressure to remove the THF and methanol. Thesolid present was collected by filtration, rinsed with water and driedunder reduced pressure at 60° C. to give the title compound (204 mg,94%) as a yellow solid, mp 289-291° C. Elemental Analysis forC₂₉H₂₁NO₅.0.40 C₄H₈O.0.22H₂O Calc'd: C, 74.06; H, 5.00; N, 2.82. Found:C, 73.83; H, 5.19; N, 2.70.

Example 18 Primary Screen for the PAI-1 Inhibition

Test compounds are dissolved in DMSO at a final concentration of 10 mM,then diluted 100× in physiologic buffer. The inhibitory assay isinitiated by the addition of the test compound (1-100 μM finalconcentration, maximum DMSO concentration of 0.2%) in a pH 6.6 buffercontaining 140 nM recombinant human plasminogen activator inhibitor-1(PAI-1; Molecular Innovations, Royal Oak, Mich.). Following a 1 hourincubation at room temperature, 70 nM of recombinant human tissueplasminogen activator (tPA) is added, and the combination of the testcompound, PAI-1 and tPA is incubated for an additional 30 minutes.Following the second incubation, Spectrozyme-tPA (American Diagnostica,Greenwich, Conn.), a chromogenic substrate for tPA, is added andabsorbance read at 405 nm at 0 and 60 minutes. Relative PAI-1 inhibitionis equal to the residual tPA activity in the presence of the testcompound and PAI-1. Control treatments include the complete inhibitionof tPA by PAI-1 at the molar ratio employed (2:1), and the absence ofany effect of the test compound on tPA alone.

Example 19 Assay for Determining IC₅₀ of Inhibition of PAI-1

This assay is based upon the non-SDS dissociable interaction between tPAand active PAI-1. Assay plates are initially coated with human tPA (10μg/ml). Test compounds of the present invention are dissolved in DMSO at10 mM, then diluted with physiologic buffer (pH 7.5) to a finalconcentration of 1-50 μM. Test compounds are incubated with human PAI-1(50 ng/ml) for 15 minutes at room temperature. The tPA-coated plate iswashed with a solution of 0.05% Tween 20 and 0.1% BSA, then the plate isblocked with a solution of 3% BSA. An aliquot of thepyrrolo-naphthyl/PAI-1 solution is then added to the tPA-coated plate,incubated at room temperature for 1 hour, and washed. Active PAI-1 boundto the plate is assessed by adding an aliquot of a 1:1000 dilution ofthe 33B8 monoclonal antibody against human PAI-1, and incubating theplate at room temperature for 1 hour (Molecular Innovations, Royal Oak,Mich.). The plate is again washed, and a solution of goat anti-mouseIgG-alkaline phosphatase conjugate is added at a 1:50,000 dilution ingoat serum. The plate is incubated 30 minutes at room temperature,washed, and a solution of alkaline phosphatase substrate is added. Theplate is incubated 45 minutes at room temperature, and color developmentis determined at OD_(405nm). The quantitation of active PAI-1 bound totPA at varying concentrations of the test compound is used to determinethe IC₅₀. Results are analyzed using a logarithmic best-fit equation.The assay sensitivity is 5 ng/ml of human PAI-1 as determined from astandard curve ranging from 0-100 ng/ml.

The compounds of the present invention inhibited Plasminogen ActivatorInhibitor-1 as summarized in Table 1. TABLE I IC₅₀ (Antibody)^(a) %Inhibition Example μM 25 μM 10 μM 1 44.4 78 12 2 16.1 66 37 3 33.02 5215 4 67 11 5 32 15 6 74 14 7 95 30 8 62 43 9 49 31 10 55 29 11 68 30 1258 48 13 60 33 14 31 23 15 68 30 16 63 40 17 44 18^(a)The IC₅₀ was determined by the Antibody Assay as described above.

Although the foregoing invention has been described in detail by way ofexample for purposes of clarity of understanding, it will be apparent tothe artisan that certain changes and modifications are comprehended bythe disclosure and can be practiced without undue experimentation withinthe scope of the appended claims, which are presented by way ofillustration not limitation.

All publications and patent documents cited above are herebyincorporated by reference in their entirety for all purposes to the sameextent as if each were so individually denoted.

1. A method for treating impairment of the fibrinolytic system,cardiovascular disease, atherosclerotic plaque formation, chronicobstructive pulmonary disease, polycystic ovary syndrome, diabetes,Alzheimer's disease, or cancer comprising administering to a subject inneed thereof a therapeutically effective amount of the compound ofFormula 1:

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof; wherein: Ar is aryl or heteroaryl; R₁ is hydrogen, C₁-C₁₂alkyl, C₆₋₁₄ aryl, C₆₋₁₄ar(C₁₋₆)alkyl, —(CH₂)_(p)-heteroaryl,—(CH₂)_(p)—CO-aryl, —(CH₂)_(p)—CO-heteroaryl,—(CH₂)_(p)—CO—(C₁-C₆)alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, or C₃-C₈cycloalkyl. R₂ and R₃ are independently hydrogen, C₁-C₁₂ alkyl, C₆₋₁₄aryl, C₆₋₁₄ar(C₁₋₆)alkyl, —(CH₂)_(p)-heteroaryl, halogen, C₁-C₆ alkoxy,aralkyl, alkoxyaryl, nitro, carboxy(C₁-C₆ alkyl), carbamide, carbamate,or C₃-C₈ cycloalkyl; R₄ is —CH(R₆)(CH₂)_(n)R₅, —C(CH₃)₂R₆,—CH(R₅)(CH₂)_(n)R₆, —CH(R₅)C₆H₄R₆, —CH(R₅)C₆H₃(CO₂H)₂,CH(R₅)C₆H₂(CO₂H)₃, or an acid mimic; R₅ is hydrogen, C₁-C₆ alkyl, C₆-C₁₂aryl, aralkyl, C₃-C₈ cycloalkyl, or —(CH₂)_(n)(R₇); R₆ is CO₂H,tetrazole, or PO₃H; R₇ is

n is from 0 to 6; p is from 0 to 3; b is from 0 to 6; and a is from 0 to6.
 2. The method of claim 1 wherein C₁₋₁₂ alkyl is unsubstituted C₁₋₁₂alkyl or C₁₋₃ perfluoroalkyl; C₁₋₆ alkoxy is unsubstituted C₁₋₆ alkoxyor C₁₋₃ perfluoroalkoxy; and said aralkyl group is unsubstituted benzylor benzyl substituted with from 1 to 3 groups selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, C₃-C₆ cycloalkyl,—(CH₂)_(p)—C₃-C₆ cycloalkyl, halogen, C₁-C₃ perfluoroalkyl, C₁-C₃perfluoroalkoxy, —(CH₂)_(p)-phenyl, and —O(CH₂)_(p)-phenyl.
 3. Themethod of claim 1 wherein the compound is of Formula 2

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof.
 4. The method of claim 1 wherein the compound is of Formula 3:

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof.
 5. The method of claim 1 wherein the compound is of Formula 4:

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof.
 6. The method of claim 1 wherein the compound is of Formula 5:

or a solvate, hydrate or pharmaceutically acceptable salt or ester formthereof wherein R₈, R₉, R₁₀, R₁₁ and R₁₂ are independently hydrogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy, C₆₋₁₄ar(C₁₋₆)alkyl, C₃-C₆cycloalkyl, —(CH₂)_(p)—C₃-C₆ cycloalkyl, halogen, —(CH₂)_(p)-phenyl, or—O(CH₂)_(p)-phenyl.
 7. The method of claim 6 wherein C₁₋₆ alkyl isunsubstituted C₁₋₆ alkyl or C₁₋₃ perfluoroalkyl and C₁₋₆ alkoxy isunsubstituted C₁₋₆ alkoxy or C₁₋₃ perfluoroalkoxy.
 8. The method ofclaim 1, wherein: Ar is aryl or heteroaryl; R₁ is hydrogen, C₁-C₆ alkylor —(CH₂)_(p)-phenyl; R₂ and R₃ are independently hydrogen,unsubstituted C₁-C₆ alkyl, phenyl-(CH₂)_(p)—, halogen or C₁-C₃perfluoroalkyl; R₄ is —CHR₅CO₂H, —CHR₅C₆H₄CO₂H, —CHR₅C₆H₃(CO₂H)₂,—CH₂-tetrazole or an acid mimic; R₅ is hydrogen, phenyl, or benzyl, andp is from 0 to
 3. 9. The method of claim 1 wherein Ar is phenyl,naphthyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, indolyl,pyrazolyl, oxazolyl or fluorenyl.
 10. The method of claim 1 wherein R₄is —CHR₅CO₂H.
 11. The method of claim 1 wherein R₄ is —(CH₂)-tetrazole.12. The method of claim 1 wherein R₄ is —CH(R₅)C₆H₄CO₂H.
 13. The methodof claim 1 wherein the compound is:3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acidor a pharmaceutically acceptable salt or ester form thereof;2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof;{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or apharmaceutically acceptable salt or ester form thereof;2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof; or3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoicacid or a pharmaceutically acceptable salt or ester form thereof. 14.The method of claim 1 wherein the compound is:[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]aceticacid or a pharmaceutically acceptable salt or ester form thereof;{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or apharmaceutically acceptable salt or ester form thereof;2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoicacid or a pharmaceutically acceptable salt or ester form thereof;5-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole ora pharmaceutically acceptable salt or ester form thereof; or5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof.
 15. Themethod of claim 1 wherein the compound is:5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;5-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazoleor a pharmaceutically acceptable salt or ester form thereof;4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoicacid or a pharmaceutically acceptable salt or ester form thereof; or4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acidor a pharmaceutically acceptable salt or ester form thereof.
 16. Themethod of claim 1 wherein the compound is:4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalicacid or a pharmaceutically acceptable salt or ester form thereof or4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acidor a pharmaceutically acceptable salt or ester form thereof.
 17. Themethod of claim 1 wherein the therapeutically effective amount is fromabout 25 mg/kg to about 200 mg/kg.
 18. The method of claim 1 wherein thecardiovascular disease is caused by noninsulin dependent diabetesmellitus in a subject.
 19. The method of claim 1 wherein the cancer isbreast or ovarian cancer.
 20. The method of claim 1 for the treatment ofdiabetes.